Tricyclic compounds and compositions as kinase inhibitors

ABSTRACT

The present invention provides compounds of Formula (A): (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent, and methods of using the compositions and combinations to treat conditions including cancers.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 U.S. national phase application ofinternational application number PCT/IB2016/057633 filed 14 Dec. 2016,which application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62/269,252, filed 18Dec. 2015, the disclosures of which are incorporated herein by referencein their entirety and for all purposes.

FIELD OF THE INVENTION

The invention provides compounds that inhibit Raf kinases, and areaccordingly useful for treating certain disorders associated withexcessive Raf kinase activity, including cell proliferation disorderssuch as cancers. The invention further provides pharmaceuticalcompositions containing these compounds and methods of using thesecompounds to treat conditions including cancer.

BACKGROUND

Protein Kinases are involved in very complex signaling cascades thatregulate most cellular functions, including cell survival andproliferation. These signaling pathways have been heavily studied,particularly in the context of disorders caused by dysregulated cellularfunction, such as cancer. The mitogen-activated protein kinase (MAPK)cascade has been studied extensively, for example, and kinases in thispathway (e.g., RAS, RAF, MEK, and ERK) have been exploited as targetsites for drug discovery. Mutated B-Raf is found in a significantfraction of malignancies (over 30% of all tumors and 40% of melanomas),and several drug candidates that inhibit a common B-Raf mutant (V600E,an activating mutation found in many cancers, particularly in cutaneousmalignant melanoma, thyroid cancer, colorectal cancer, and ovariancancer) have been reported, including GDC-0879, PLX4032, and PLX4720,while other inhibitors targeting C-Raf or B-Raf (or both) includesorafenib, XL281 RAF265, and BAY43-9006. These examples demonstrate thatcompounds that inhibit B-Raf or C-Raf are useful to treat variouscancers.

The MAPK signaling cascade includes RAS, Raf, MEK and ERK kinases, eachof which is actually a group of related proteins. These proteinsfunction collectively as a signal transduction cascade where the numberof distinct kinases and their varying substrate specificities create acomplex and highly branched pathway. Raf, for example, consists ofmonomers referred to as A-Raf, B-Raf, and C-Raf (also called Raf-1),each of which functions primarily as a dimer. The RAF complex includesheterodimers as well as homodimers of these three species, bringing thetotal number of dimeric species in the Raf group to six, with each ofthese having a number of sites where phosphorylation at serine,threonine or tyrosine can cause either activation or inhibition. Due tothe complexity of the pathway and its regulation, it has been reportedthat inhibitors of B-Raf can cause paradoxical activation of thepathway, apparently due to conformational effects on the kinase domainof Raf that affect dimerization, membrane localization, and interactionwith RAS-GTP. In particular, ATP-competitive inhibitors can exhibitopposing effects on the signaling pathway, as either inhibitors oractivators, depending on the cellular context. As a result, B-Rafinhibitors effective against tumors having the activating B-Raf mutationV600E may not be as effective as expected in tumors having wild-typeB-Raf or KRas mutations.

The present invention provides novel inhibitors of Raf kinases,including A-Raf, B-Raf and/or C-Raf, and use of these compounds to treatdisorders associated with excessive or undesired levels of Raf activity,such as certain cancers. The compounds of the invention minimizeundesired pathway activation effects, and thus can be more efficaciousand more predictable in vivo than the B-Raf inhibitors that causeparadoxical pathway activation even when they have similar in vitropotency. The compounds of the invention bind in a DFG-out mode, makingthem type 2 inhibitors, which have been reported to be less prone toinduce paradoxical activation. The compounds are suited for treatment ofBRaf wild-type and KRas mutant tumors, as well as B-Raf V600E mutanttumors.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of the formula (A):

in which:

-   -   R′ is selected from H and methyl;    -   R₁ is C₁₋₃alkyl substituted by CN or by one or more halogens;    -   R₂ is selected from:

-   -   -   wherein Z₁ is CR₃R₄, —O—, a bond, or CR₇; provided that when            Z₁ is CR₇, Z₁ is attached by a double bond to the carbon            atom nearing R₉ and R₉ is absent;        -   Z₂ is CR₅R₆, O, —C(O)NR₈—[Y₆], —NR₈C(O)—[Y₆], or            —(CR₇)₀₋₁—C(O)—[Y₆], where [Y₆] indicates which atom of Z₂            is attached to the ring containing Y₆; provided Z₁ and Z₂            are not both simultaneously O;        -   Z₃ is a carbon atom bonded to Y₆ by an aromatic bond, or Z₃            is a nitrogen atom bonded to Y₆ by a single bond;

    -   R₃ is selected from hydrogen, C₁₋₃alkyl, halo,        C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl        and hydroxy-substituted-C₁₋₃alkyl;

    -   R₄ is selected from hydrogen, amino, C₁₋₃alkyl, cyano,        hydroxy-ethyl and halo; or R₃ and R₄ together with the carbon        atom to which R₃ and R₄ are attached form a 4 member saturated        cyclic ring containing an oxygen molecule;

    -   R₅ is selected from hydrogen, halo, amino,        C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, hydroxy and        C₁₋₃alkoxy;

    -   R₆ is selected from hydrogen, C₁₋₃alkyl, halo,        halo-substituted-C₁₋₃alkyl; or R₄ and R₆ together with the        carbon atom to which R₄ and R₆ are attached form 5-6 member        unsaturated ring containing up to 2 heteroatoms selected from O,        S and N; wherein said ring is optionally substituted with        C₁₋₂alkyl;

    -   R₇ is selected from hydrogen, hydroxy-carbonyl and        C₁₋₃alkoxy-carbonyl;

    -   R₈ is selected from hydrogen, C₁₋₃alkyl-amino-carbonyl,        C₁₋₃alkyl-carbonyl, C₁₋₃alkoxy and        hydroxy-substituted-C₁₋₄alkoxy, hydroxy-substituted-C₁₋₃alkyl,        and C₁₋₃alkyl;

    -   R₉ is independently selected at each occurrence from hydrogen,        fluorine, and methyl;

    -   each R₁₀ represents an optional substituent selected from C₁₋₃        alkyl and C₁₋₃ alkoxy, or two R₁₀ on non-adjacent ring atoms can        be taken together to form a bond or a (CH₂)₁₋₂ bridge linking        the two non-adjacent ring atoms to form a fused or bridged ring;

    -   Y₀ is selected from N, CH and CF;

    -   Y₁ is selected from N and CH;

    -   Y₂ is selected from N, CH, CF, CCl, C—NH₂, and C—C(R₉)₂NH₂;

    -   Y₃ is selected from N and CH;

    -   Y₄ is selected from N and CH;

    -   Y₅ is selected from N and CH; and

    -   Y₆ is selected from N and CH when Z₃ is carbon, and Y₆ is C(═O)        when Z₃ is nitrogen;

    -   or a pharmaceutically acceptable salt thereof.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula (A) or a N-oxidederivative, individual isomers and mixture of isomers thereof, includingsubgenera of Formula (A) described herein; or a pharmaceuticallyacceptable salt thereof, in admixture with one or more suitableexcipients.

In another aspect, the compounds of Formula (A) are inhibitors of Rafkinases as shown by data herein, and are accordingly useful to treatconditions such as melanoma, breast cancer, sarcoma, GI tumors such asgastrointestinal stromal tumors, ovarian cancer, sarcoma, GI tumors suchas gastrointestinal stromal tumors, and other malignancies associatedwith excessive Raf pathway activity, particularly in cancers driven byRas mutations. In addition, the compounds of the invention exhibit lowlevels of paradoxical activation of the Raf pathway.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of Formula (A) admixed with at least onepharmaceutically acceptable carrier or excipient, optionally admixedwith two or more pharmaceutically acceptable carriers or excipients.

In addition, the invention includes combinations of a compound ofFormula (A) with a co-therapeutic agent, optionally including one ormore pharmaceutically acceptable carriers, and methods of treatmentusing a compound of Formula (A) or Formula (I) or any of the sub-formulathereof described herein in combination with a co-therapeutic agent.Suitable co-therapeutic agents for use in the invention include, forexample, cancer chemotherapeutics including but not limited toinhibitors of PI3K, other inhibitors of the Raf pathway, paclitaxel,docetaxel, temozolomide, platins, doxorubicins, vinblastins,cyclophosphamide, topotecan, gemcitabine, ifosfamide, etoposide,irinotecan, and the like.

In another aspect, the invention provides a method to treat a conditioncharacterized by excessive or undesired levels of activity of Raf,especially B-Raf and/or C-Raf, which comprises administering to asubject in need of such treatment an effective amount of a compound ofFormula (A) or any subgenus thereof as described herein, or apharmaceutical composition comprising such compound. The subject can bea mammal, and is preferably a human. Conditions treatable by thecompounds and methods described herein include various forms of cancer,such as solid tumors, melanoma, breast cancer, lung cancer (e.g.,non-small cell lung cancer), sarcoma, GI tumors such as gastrointestinalstromal tumors, ovarian cancer, colorectal cancer, thyroid cancer, andpancreatic cancer. The invention thus includes compounds of Formula (A)or (I) and the subgenera thereof that are disclosed herein, includingeach species disclosed herein, for use in therapy, particularly for useto treat cancers such as melanoma, breast cancer, lung cancer, livercancer, sarcoma, GI tumors such as gastrointestinal stromal tumors,sarcoma, GI tumors such as gastrointestinal stromal tumors, ovariancancer, colorectal cancer, thyroid cancer, and pancreatic cancer. Theinvention also includes use of such compounds for manufacture of amedicament for treating these conditions.

The invention includes compounds of Formula (A) and the subgenera ofFormula (A) described herein, and all stereoisomers (includingdiastereoisomers and enantiomers), tautomers and isotopically enrichedversions thereof (including deuterium substitutions), as well aspharmaceutically acceptable salts of these compounds. In particular,where a heteroaryl ring containing N as a ring atom is optionallysubstituted with hydroxyl, e.g., a 2-hydroxypyridine ring, tautomerswhere the hydroxyl is depicted as a carbonyl (e.g., 2-pyridone) areincluded. Compounds of the present invention also comprise polymorphs ofcompounds of formula (A) (or sub-formulae thereof) and salts thereof.

DETAILED DESCRIPTION

The following definitions apply unless otherwise expressly provided.

As used herein, the term “halogen” (or halo) refers to fluorine,bromine, chlorine or iodine, in particular fluorine or chlorine.Halogen-substituted groups and moieties, such as alkyl substituted byhalogen (haloalkyl) can be mono-, poly- or per-halogenated.

As used herein, the term “hetero atoms” refers to nitrogen (N), oxygen(O) or sulfur (S) atoms, in particular nitrogen or oxygen, unlessotherwise provided.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having up to 20 carbon atoms. Unlessotherwise provided, alkyl refers to hydrocarbon moieties having 1 to 10carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Typically,alkyl groups have 1-6 carbon atoms. “Lower alkyl” refers to alkyl groupshaving 1-4 carbon atoms. Representative examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

A substituted alkyl is an alkyl group containing one or moresubstituents in place of hydrogen, such as one, two or threesubstituents, or 1-4 substituents, up to the number of hydrogens presenton the unsubstituted alkyl group. Suitable substituents for alkylgroups, if not otherwise specified, may be selected from halogen, CN,oxo, hydroxy, substituted or unsubstituted C₁₋₄ alkoxy, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆heterocycloalkyl, substituted or unsubstituted phenyl, amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl,—C(═O)—C₁₋₄ alkyl, COOH, COO(C₁₋₄ alkyl), —O(C═O)—C₁₋₄ alkyl,—NHC(═O)C₁₋₄ alkyl and —NHC(═O)OC₁₋₄ alkyl groups; wherein thesubstituents for substituted C₁₋₄ alkoxy, substituted C₃₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl, and substituted phenyl are up to three groupsselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, amino,hydroxy, and CN. Preferred substituents for alkyl groups includehalogen, CN, oxo, hydroxy, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, phenyl, amino,(C₁₋₄ alkyl)amino, di(C₁₋₄ alkyl)amino, C₁₋₄ alkylthio, C₁₋₄alkylsulfonyl, —C(═O)—C₁₋₄ alkyl, COOH, —COO(C₁₋₄ alkyl), —O(C═O)—C₁₋₄alkyl, —NHC(═O)C₁₋₄ alkyl and —NHC(═O)OC₁₋₄ alkyl groups.

As used herein, the term “alkylene” refers to a divalent alkyl grouphaving 1 to 10 carbon atoms, and two open valences to attach to otherfeatures. Unless otherwise provided, alkylene refers to moieties having1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.Representative examples of alkylene include, but are not limited to,methylene, ethylene, n-propylene, iso-propylene, n-butylene,sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene,neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene,2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decyleneand the like. A substituted alkylene is an alkylene group containing oneor more, such as one, two or three substituents; unless otherwisespecified, suitable and preferred substituents are selected from thesubstituents described as suitable and preferred for alkyl groups.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, which is substituted by one or more halo groups as definedherein. The haloalkyl can be monohaloalkyl, dihaloalkyl, trihaloalkyl,or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have oneiodo, bromo, chloro or fluoro within the alkyl group. Chloro and fluoroare preferred on alkyl or cycloalkyl groups; fluoro, chloro and bromoare often preferred on aryl or heteroaryl groups. Dihaloalkyl andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Typically thepolyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Non-limiting examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhalo-alkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms, e.g,trifluoromethyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined above. Representative examples of alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy,pentyloxy, hexyloxy, and the like. Typically, alkoxy groups have 1-10,or 1-6 carbons, more commonly 1-4 carbon atoms.

A “substituted alkoxy” is an alkoxy group containing one or more, suchas one, two or three substituents on the alkyl portion of the alkoxy.Unless otherwise specified, suitable and preferred substituents areselected from the substituents listed above for alkyl groups, exceptthat hydroxyl and amino are not normally present on the carbon that isdirectly attached to the oxygen of the substituted ‘alkyl-O’ group.

Similarly, each alkyl part of other groups like “alkylaminocarbonyl”,“alkoxyalkyl”, “alkoxycarbonyl”, “alkoxy-carbonylalkyl”,“alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”, “haloalkyl” shall havethe same meaning as described in the above-mentioned definition of“alkyl”. When used in this way, unless otherwise indicated, the alkylgroup is often a 1-4 carbon alkyl and is not further substituted bygroups other than the component named. When such alkyl groups aresubstituted, suitable substituents are selected from the suitable orpreferred substituents named above for alkyl groups unless otherwisespecified.

As used herein, the term “haloalkoxy” refers to haloalkyl-O—, whereinhaloalkyl is defined above. Representative examples of haloalkoxyinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, trichloromethoxy, 2-chloroethoxy,2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, and the like.Typically, haloalkyl groups have 1-4 carbon atoms.

Description of Embodiments

The present invention provides compounds, compositions and methods forthe treatment of kinase related disease, particularly Raf kinase relateddiseases; for example: various forms of cancer, such as solid tumors,melanoma, breast cancer, lung cancer (e.g., non-small cell lung cancer),sarcoma, GI tumors such as gastrointestinal stromal tumors, ovariancancer, colorectal cancer, thyroid cancer, and pancreatic cancer.Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments of thepresent invention. The following embodiments are representative of theinvention.

1. A compound of formula (A):

-   -   in which:    -   R′ is selected from H and methyl;    -   R₁ is C₁₋₃alkyl substituted by CN or by one or more halogens;    -   R₂ is selected from:

-   -   -   wherein Z₁ is CR₃R₄, —O—, a bond, or CR₇; provided that when            Z₁ is CR₇, Z₁ is attached to the carbon atom bonded to R₉ by            a double bond and R₉ is absent;        -   Z₂ is CR₅R₆, O, —C(O)NR₈—[Y₆], —NR₈C(O)—[Y₆], or            —(CR₇)₀₋₁—C(O)—[Y₆], where [Y₆] indicates which atom of Z₂            is attached to the ring containing Y₆; provided Z₁ and Z₂            are not both simultaneously O;        -   Z₃ is a carbon atom bonded to Y₆ by an aromatic bond, or Z₃            is a nitrogen atom bonded to Y₆ by a single bond;

    -   R₃ is selected from hydrogen, C₁₋₃alkyl, halo,        C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl        and hydroxy-substituted-C₁₋₃alkyl;

    -   R₄ is selected from hydrogen, amino, C₁₋₃alkyl, cyano,        hydroxy-ethyl and halo; or R₃ and R₄ together with the carbon        atom to which R₃ and R₄ are attached form a 4 member saturated        cyclic ring containing an oxygen molecule;

    -   R₅ is selected from hydrogen, halo, amino,        C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, hydroxy and        C₁₋₃alkoxy;

    -   R₆ is selected from hydrogen, C₁₋₃alkyl, halo,        halo-substituted-C₁₋₃alkyl; or R₄ and R₆ together with the        carbon atom to which R₄ and R₆ are attached form 5-6 member        unsaturated ring containing up to 2 heteroatoms selected from O,        S and N; wherein said ring is optionally substituted with        C₁₋₂alkyl;

    -   R₇ is selected from hydrogen, hydroxy-carbonyl and        C₁₋₃alkoxy-carbonyl;

    -   R₈ is selected from hydrogen, C₁₋₃alkyl-amino-carbonyl,        C₁₋₃alkyl-carbonyl, C₁₋₃alkoxy and        hydroxy-substituted-C₁₋₄alkoxy, hydroxy-substituted-C₁₋₃alkyl,        and C₁₋₃alkyl;

    -   R₉ is independently selected at each occurrence from hydrogen,        fluorine, and methyl;

    -   each R₁₀ represents an optional substituent selected from C₁₋₃        alkyl and C₁₋₃ alkoxy, or two R₁₀ on non-adjacent ring atoms can        be taken together to form a bond or a (CH₂)₁₋₂ bridge linking        the two non-adjacent ring atoms to form a fused or bridged ring;

    -   Y₀ is selected from N, CH and CF;

    -   Y₁ is selected from N and CH;

    -   Y₂ is selected from N, CH, CF, CCl, C—NH₂, and C—C(R₉)₂NH₂;

    -   Y₃ is selected from N and CH;

    -   Y₄ is selected from N and CH;

    -   Y₅ is selected from N and CH; and

    -   Y₆ is selected from N and CH when Z₃ is carbon, and Y₆ is C(═O)        when Z₃ is nitrogen;

    -   or a pharmaceutically acceptable salt thereof.        2. The compound of embodiment 1, wherein R′ is methyl.        3. The compound of embodiment 1 or 2, wherein Y₄ is CH.        4. The compound of embodiment 1 or 2, wherein Y₄ is N.        5. The compound of any of the preceding embodiments, wherein Y₀        is CH.        6. The compound of any of the preceding embodiments, wherein Y₁        is N.        7. The compound of any of the preceding embodiments, wherein Y₂        is CH.        8. The compound of any of the preceding embodiments, wherein Y₃        is CH

-   9. The compound of any of the preceding embodiments, wherein Y₅ is    CH.    10. The compound of any of the preceding embodiments, wherein Y₆ is    CH.    11. The compound of any of the preceding embodiments, wherein R₉ is    H.    12. The compound of any of the preceding embodiments, wherein Z₁ is    CH₂ or a bond.    13. The compound of any of the preceding embodiments, wherein R₂ is    selected from:

-   -   wherein Y₆ is selected from N and CH;    -   Z₁ is CR₃R₄ or a bond; and    -   Z₂ is CR₅R₆, —C(O)NR₈—[Y₆] or —NR₈C(O)—[Y₆], where [Y₆]        indicates which atom of Z₂ is attached to the ring containing        Y₆.        14. The compound of embodiment 1, which is of the formula (I):

-   -   in which:    -   R′ is selected from H and methyl;    -   R₁ is selected from halo-substituted C₁₋₃alkyl;    -   R₂ is selected from:

and optionally also

-   -   R₃ is selected from hydrogen, C₁₋₃alkyl, halo,        C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl        and hydroxy-substituted-C₁₋₃alkyl;    -   R₄ is selected from hydrogen, amino, C₁₋₃alkyl, cyano,        hydroxy-ethyl and halo; or R₃ and R₄ together with the carbon        atom to which R₃ and R₄ are attached form a 4 member saturated        cyclic ring containing an oxygen molecule;    -   R₅ is selected from hydrogen, halo, amino,        C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, hydroxy and        C₁₋₃alkoxy;    -   R₆ is selected from hydrogen, C₁₋₃alkyl, halo,        halo-substituted-C₁₋₃alkyl; or R₄ and R₆ together with the        carbon atom to which R₄ and R₆ are attached form 5-6 member        unsaturated ring containing up to 2 heteroatoms selected from O,        S and N; wherein said ring is optionally substituted with        C₁₋₂alkyl; each    -   R₇ is selected from hydrogen, hydroxy-carbonyl and        C₁₋₃alkoxy-carbonyl;    -   R₈ is selected from hydrogen, C₁₋₃alkyl-amino-carbonyl,        C₁₋₃alkyl-carbonyl, C₁₋₃alkoxy and        hydroxy-substituted-C₁₋₄alkoxy and C₁₋₃alkyl;    -   R₉ is selected from hydrogen and methyl;    -   Y₁ is selected from N and CH;    -   Y₂ is selected from N and CH;    -   Y₃ is selected from N and CH;    -   Y₄ is selected from N and CH;    -   Y₅ is selected from N and CH; and    -   Y₆ is selected from N and CH; or the pharmaceutically acceptable        salt thereof.

In a 15th embodiment, with reference to compounds of formula I, arecompounds of formula (Ia):

in which:

R₁ is selected from halo-substituted C₁₋₃alkyl; R₈ is selected fromhydrogen and C₁₋₃alkyl; R₉ is selected from hydrogen and methyl; Y₁ isselected from N and CH; Y₂ is CH; Y₃ is CH; Y₄ is selected from N andCH; Y₅ is selected from N and CH; and Y₆ is selected from N and CH; orthe pharmaceutically acceptable salt thereof.

In a 16th embodiment, R₁ is selected from trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; R₈ isselected from hydrogen and ethyl; Y₁ is selected from N and CH; Y₄ isselected from N and CH; Y₅ is selected from N and CH; and Y₆ is selectedfrom N and CH; or the pharmaceutically acceptable salt thereof. Specificcompounds of this embodiment are selected from the following compoundsand their pharmaceutically acceptable salts:

In a 17th embodiment, with reference to compounds of formula I, arecompounds of formula (Ib):

in which: R₁ is selected from halo-substituted C₁₋₃alkyl; R₃ is selectedfrom hydrogen, C₁₋₃alkyl, halo, C₁₋₃alkyl-amino-carbonyl,C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl and hydroxy-substituted-C₁₋₃alkyl;R₄ is selected from hydrogen, amino, C₁₋₃alkyl, cyano, hydroxy-ethyl andhalo; or R₃ and R₄ together with the carbon atom to which R₃ and R₄ areattached form a 4 member saturated cyclic ring containing an oxygenmolecule; R₅ is selected from hydrogen, halo, amino,C₁₋₃alkyl-amino-carbonyl, hydroxy and C₁₋₃alkoxy; R₆ is selected fromhydrogen, C₁₋₃alkyl, halo, halo-substituted-C₁₋₃alkyl; or R₄ and R₆together with the carbon atom to which R₄ and R₆ are attached form 5-6member unsaturated ring containing up to 2 heteroatoms selected from O,S and N; wherein said ring is optionally substituted with C₁₋₃alkyl; R₉is selected from hydrogen and methyl; Y₁ is selected from N and CH; Y₂is selected from N and CH; Y₃ is selected from N and CH; Y₄ is selectedfrom N and CH; Y₅ is selected from N and CH; and Y₆ is selected from Nand CH; or the pharmaceutically acceptable salt thereof.

In an 18th embodiment, R₁ is selected from trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; R₃ isselected from hydrogen and methyl, fluoro, methyl-amino-carbonyl,ethyl-amino-carbonyl, methyl-sulfonyl-methyl, carboxyl andhydroxy-ethyl; R₄ is selected from hydrogen, methyl, cyano, amino,hydroxy-ethyl and fluoro; or R₃ and R₄ together with the carbon atom towhich R₃ and R₄ are attached form oxetan-3-yl; R₅ is selected fromhydrogen, fluoro, amino, methyl-carbonyl-amino, ethyl-carbonyl-amino,hydroxy and methoxy; R₆ is selected from hydrogen, methyl, fluoro andtrifluoromethyl; or R₄ and R₆ together with the carbon atom to which R₄and R₆ are attached form pyrazolyl optionally substituted with methyl;R₉ is selected from hydrogen and methyl; Y₁ is selected from N and CH;Y₂ is CH; Y₃ is CH; Y₄ is selected from N and CH; Y₅ is selected from Nand CH; and Y₆ is selected from N and CH; or the pharmaceuticallyacceptable salt thereof.

Particular examples of this embodiment are compounds, or thepharmaceutically acceptable salt thereof, selected from:

In a 19th embodiment, with reference to compounds of formula (I), arecompounds of formula (Ic):

in which: R₁ is selected from halo-substituted C₁₋₃alkyl; R₈ is selectedfrom hydrogen and C₁₋₃alkyl; R₉ is selected from hydrogen and methyl; Y₁is selected from N and CH; Y₂ is selected from N and CH; Y₃ is selectedfrom N and CH; Y₄ is selected from N and CH; Y₅ is selected from N andCH; and Y₆ is selected from N and CH; or the pharmaceutically acceptablesalt thereof.

In a subset of this embodiment, R₁ is selected from trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; R₈ isselected from hydrogen and ethyl; R₉ is selected from hydrogen andmethyl; Y₁ is selected from N and CH; Y₂ is CH; Y₃ is CH; Y₄ is selectedfrom N and CH; Y₅ is selected from N and CH; and Y₆ is selected from Nand CH; or the pharmaceutically acceptable salt thereof.

In particular examples of this embodiment are compounds, or thepharmaceutically acceptable salt thereof, selected from:

In a 21st embodiment, with reference to compounds of formula (I), arecompounds of formula (Id):

in which: R₁ is selected from halo-substituted C₁₋₃alkyl; each R₇ isselected from hydrogen, C₁₋₂alkoxy-carbonyl and hydroxy-carbonyl; Y₁ isselected from N and CH; Y₂ is CH; Y₃ is CH; and Y₄ is selected from Nand CH; or the pharmaceutically acceptable salt thereof.

In a 22nd embodiment, R₁ is selected from trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; each R₇is selected from hydrogen, ethoxy-carbonyl and hydroxy-carbonyl; Y₁ isselected from N and CH; Y₂ is CH; Y₃ is CH; and Y₄ is selected from Nand CH; or the pharmaceutically acceptable salt thereof.

In particular examples of this embodiment are compounds, or thepharmaceutically acceptable salt thereof, selected from:

In a 23rd embodiment, with reference to compounds of formula (I), arecompounds of formula (Ie):

in which: R₁ is selected from halo-substituted C₁₋₃alkyl; R₃ is selectedfrom hydrogen and C₁₋₃alkyl; R₄ is selected from hydrogen and C₁₋₃alkyl;Y₁ is selected from N and CH; Y₂ is selected from N and CH; Y₃ isselected from N and CH; Y₄ is selected from N and CH; Y₅ is selectedfrom N and CH; and Y₆ is selected from N and CH; or the pharmaceuticallyacceptable salt thereof.

In a subset of this embodiment, R₁ is selected from trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; R₃ isselected from hydrogen, methyl and ethyl; R₄ is selected from hydrogen,methyl and ethyl; Y₁ is N; Y₂ is CH; Y₃ is CH; Y₄ is CH; Y₅ is N; and Y₆is N; or the pharmaceutically acceptable salt thereof.

In particular examples of this embodiment are compounds, or thepharmaceutically acceptable salt thereof, selected from:

In a 25th embodiment, with reference to compounds of formula (I), arecompounds of formula (If):

in which: R₁ is selected from trifluoromethyl, 2-fluoropropan-2-yl,2-cyanopropan-2-yl and 1,1-difluoroethyl; R₃ is selected from hydrogenand C₁₋₃alkyl; R₄ is selected from hydrogen and C₁₋₃alkyl; R₅ isselected from hydrogen, halo, amino, C₁₋₃alkyl-amino-carbonyl, hydroxyand C₁₋₃alkoxy; R₆ is selected from hydrogen, C₁₋₃alkyl, halo andhalo-substituted-C₁₋₃alkyl; Y₁ is selected from N and CH; Y₂ is selectedfrom N and CH; Y₃ is selected from N and CH; and Y₄ is selected from Nand CH; or the pharmaceutically acceptable salt thereof.

Included in this embodiment are compounds, or the pharmaceuticallyacceptable salt thereof, selected from:

In a 26th embodiment, with reference to compounds of formula (I), arecompounds of formula (Ig):

in which: R₁ is selected from trifluoromethyl, 2-fluoropropan-2-yl,2-cyanopropan-2-yl and 1,1-difluoroethyl; R₈ is selected from hydrogenand C₁₋₃alkyl; Y₁ is selected from N and CH; Y₂ is selected from N andCH; Y₃ is selected from N and CH; Y₄ is selected from N and CH; Y₅ isselected from N and CH; and Y₆ is selected from N and CH; or thepharmaceutically acceptable salt thereof.

In certain examples of this embodiment are compounds, or thepharmaceutically acceptable salt thereof, selected from:

27. The compound of embodiment 1 or embodiment 14, or a pharmaceuticallyacceptable salt thereof, selected from the compound of any of Examples1-534.28. A pharmaceutical composition comprising a compound of embodiment 1or embodiment 14, or a pharmaceutically acceptable salt thereof, and oneor more pharmaceutically acceptable carriers.29. A combination comprising a therapeutically effective amount of acompound according to embodiment 1 embodiment claim 14, or apharmaceutically acceptable salt thereof, and one or moretherapeutically active co-agents.30. A method of treating a cancer, comprising administering to a subjectin need thereof a therapeutically effective amount of a compound ofembodiment 1 or embodiment 14, or a pharmaceutically acceptable saltthereof.31. The method of embodiment 30, wherein the cancer is selected frommelanoma, breast cancer, non-small cell lung cancer, lungadenocarcinoma, sarcoma, gastrointestinal stromal tumors, ovariancancer, colorectal cancer, thyroid cancer and pancreatic cancer.

Each of the Example compounds has a measured IC-50 (c-Raf) shown in theBioactivity Table below. Thus the use of any one of these compounds fortreatment of a condition selected from melanoma, breast cancer, lungcancer (e.g., non-small cell lung cancer, lung adenocarcinoma), sarcoma,GI tumors such as gastrointestinal stromal tumors, ovarian cancer,colorectal cancer, thyroid cancer, and pancreatic cancer is anembodiment of the invention.

As used herein, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. The term “chiral” refers to molecules whichhave the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner. Therefore, the inventionincludes enantiomers, diastereomers or racemates of the compound.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term is used to designate a racemic mixture whereappropriate. “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-lngold-Prelog ‘R-S’ system. When a compound is a pure enantiomer,the stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain compounds described herein contain one ormore asymmetric centers or axes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and synthesisprocedures, the compounds can be present in the form of one of thepossible isomers or as mixtures thereof, for example as pure opticalisomers, or as isomer mixtures, such as racemates and diastereoisomermixtures, depending on the number of asymmetric carbon atoms. Thepresent invention is meant to include all such possible isomers,including racemic mixtures, diasteriomeric mixtures and optically pureforms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration unless specified. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration, unless otherwise specified. All tautomeric formsare also intended to be included.

In many cases, the compounds of the present invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. As used herein, the terms“salt” or “salts” refers to an acid addition or base addition salt of acompound of the invention. “Salts” include in particular “pharmaceuticalacceptable salts”. The term “pharmaceutically acceptable salts” refersto salts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlorotheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts. Lists of additional suitable salts can be found,e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic or organic bases and can have inorganic or organiccounterions.

Inorganic counterions for such base salts include, for example, ammoniumsalts and metals from columns I to XII of the periodic table. In certainembodiments, the counterion is selected from sodium, potassium,ammonium, alkylammonium having one to four C1-C4 alkyl groups, calcium,magnesium, iron, silver, zinc, and copper; particularly suitable saltsinclude ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Suitable organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, tetrahydrofuran, toluene, chloroform, dichloromethane,methanol, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable.

Any formula given herein is also intended to represent unlabeled forms(i.e., compounds wherein all atoms are present at natural isotopicabundances, and not isotopically enriched) as well as isotopicallyenriched or labeled forms of the compounds. Isotopically enriched orlabeled compounds have structures depicted by the formulas given hereinexcept that at least one atom of the compound is replaced by an atomhaving an atomic mass or mass number different from the atomic mass orthe atomic mass distribution that occurs naturally. Examples of isotopesthat can be incorporated into enriched or labeled compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includesvarious isotopically labeled compounds as defined herein, for examplethose in which radioactive isotopes, such as ³H and ¹⁴C, or those inwhich non-radioactive isotopes, such as ²H and ¹³C, are present atlevels significantly above the natural abundance for these isotopes.These isotopically labeled compounds are useful in metabolic studies(with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H),detection or imaging techniques, such as positron emission tomography(PET) or single-photon emission computed tomography (SPECT) includingdrug or substrate tissue distribution assays, or in radioactivetreatment of patients. In particular, an ¹⁸F or labeled compound may beparticularly desirable for PET or SPECT studies. Isotopically-labeledcompounds of formula (A) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples and Preparations usingan appropriate isotopically-labeled reagents in place of the non-labeledreagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (A). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d⁶-acetone, d⁶-DMSO, as well as solvates withnon-enriched solvents.

Compounds of the invention, i.e. compounds of formula (A) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (A) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (A) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (A).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a diseasemediated by a Raf kinase such as B-Raf or C-Raf, or associated withactivity of a kinase such as B-Raf or C-Raf, or (2) reduce or inhibitthe activity of a kinase such as B-Raf or C-Raf in vivo.

In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reduce or inhibit the activity of a kinase such as B-Raf orC-Raf, or at least partially reduce or alleviate a symptom or acondition associated with excessive Raf kinase activity.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In specific embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the development or progression of the disease or disorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess ofeither the (R)- or (S)-configuration; i.e., for optically activecompounds, it is often preferred to use one enantiomer to thesubstantial exclusion of the other enantiomer. Substituents at atomswith unsaturated double bonds may, if possible, be present in cis-(Z)-or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof. ‘Substantially pure’ or‘substantially free of other isomers’ as used herein means the productcontains less than 5%, and preferably less than 2%, of other isomersrelative to the amount of the preferred isomer, by weight.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,and the like. In addition, the pharmaceutical compositions of thepresent invention can be made up in a solid form (including withoutlimitation capsules, tablets, pills, granules, powders orsuppositories), or in a liquid form (including without limitationsolutions, suspensions or emulsions). The pharmaceutical compositionscan be subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers,etc.

Typically, the pharmaceutical compositions for compounds of Formula (A)are tablets or gelatin capsules comprising an active ingredient ofFormula (A) together with at least one of the following pharmaceuticallyacceptable excipients:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurized container, pump, spray, atomizer ornebulizer, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula (A) in free form or in salt form, exhibitvaluable pharmacological activities, e.g. they modulate or inhibitactivity of A-Raf, B-Raf and/or C-Raf, as indicated by test dataprovided in the next sections, and are therefore indicated for therapyor for use as research chemicals, e.g. as tool compounds. Thesecompounds are especially useful for treatment of cancers driven bymutations in the Raf/Raf/MEK/ERK pathway, including cancerscharacterized by an activating Raf mutation such as Raf V600E, includingbut not limited to melanoma (e.g., malignant melanoma), breast cancer,lung cancer (e.g., non-small cell lung cancer), sarcoma, GI tumors suchas gastrointestinal stromal tumors, ovarian cancer, colorectal cancer,thyroid cancer, and pancreatic cancer.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (A) or any of the embodiments within the scope ofFormula (A) as described herein, in therapy. In a further embodiment,the therapy is for a disease which may be treated by inhibition ofA-Raf, B-Raf or C-Raf. In another embodiment, the compounds of theinvention are useful to treat cancers, including but not limited tomelanoma, breast cancer, lung cancer, sarcoma, GI tumors such asgastrointestinal stromal tumors, ovarian cancer, colorectal cancer,thyroid cancer, and pancreatic cancer.

In another embodiment, the invention provides a method of treating adisease which is treatable by inhibition of A-Raf, B-Raf or C-Raf, or acombination thereof, comprising administration of a therapeuticallyeffective amount of a compound of formula (A) or any of the embodimentswithin the scope of Formula (A) as described herein. In a furtherembodiment, the disease is selected from the afore-mentioned list,suitably melanoma, breast cancer, lung cancer, sarcoma, GI tumors suchas gastrointestinal stromal tumors, ovarian cancer, colorectal cancer,thyroid cancer, and pancreatic cancer. The method typically comprisesadministering an effective amount of a compound as described herein or apharmaceutical composition comprising such compound to a subject in needof such treatment. The compound may be administered by any suitablemethod such as those described herein, and the administration may berepeated at intervals selected by a treating physician.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (A) or any of the embodiments of such compoundsdescribed herein for the manufacture of a medicament. In a furtherembodiment, the medicament is for treatment of a disease which may betreated by inhibition of A-Raf, B-Raf or C-Raf. In another embodiment,the disease is a cancer, e.g., a cancer selected from theafore-mentioned list, including melanoma, breast cancer, lung cancer,sarcoma, GI tumors such as gastrointestinal stromal tumors, ovariancancer, colorectal cancer, thyroid cancer, and pancreatic cancer.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more therapeuticco-agent(s) (co-therapeutic agents). Suitable co-therapeutic agents foruse in the invention include, for example, cancer chemotherapeuticsincluding but not limited to inhibitors of PI3K, other inhibitors of theRaf pathway, paclitaxel, docetaxel, temozolomide, platins, doxorubicins,vinblastins, cyclophosphamide, topotecan, gemcitabine, ifosfamide,etoposide, irinotecan, and the like. The compound of the presentinvention may be administered separately, by the same or different routeof administration, or together in the same pharmaceutical composition asthe co-agent(s).

In one embodiment, the invention provides a product comprising acompound of formula (A) and at least one other therapeutic co-agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by B-Raf or C-Raf, such as cancer. Products providedas a combined preparation include a composition comprising the compoundof formula (A) and the other therapeutic co-agent(s) together in thesame pharmaceutical composition, or the compound of formula (A) and theother therapeutic co-agent(s) in separate form, e.g. in the form of akit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (A) and another therapeuticco-agent(s). Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (A). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic co-agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (A)for treating a disease or condition mediated by B-Raf or C-Raf, whereinthe medicament is prepared for administration with another therapeuticagent. The invention also provides the use of another therapeuticco-agent for treating a disease or condition, wherein the medicament isadministered with a compound of formula (A).

The invention also provides a compound of formula (A) for use in amethod of treating a disease or condition mediated by B-Raf or C-Raf,wherein the compound of formula (A) is prepared for administration withanother therapeutic agent. The invention also provides anothertherapeutic co-agent for use in a method of treating a disease orcondition mediated by B-Raf or C-Raf, wherein the other therapeuticco-agent is prepared for administration with a compound of formula (A).The invention also provides a compound of formula (A) for use in amethod of treating a disease or condition mediated by B-Raf or C-Raf,wherein the compound of formula (A) is administered with anothertherapeutic co-agent. The invention also provides another therapeuticco-agent for use in a method of treating a disease or condition mediatedby B-Raf or C-Raf, wherein the other therapeutic co-agent isadministered with a compound of formula (A).

The invention also provides the use of a compound of formula (A) fortreating a disease or condition mediated by B-Raf or C-Raf, wherein thepatient has previously (e.g. within 24 hours) been treated with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a disease or condition mediated by B-Rafor C-Raf, wherein the patient has previously (e.g. within 24 hours) beentreated with a compound of formula (A).

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula (A) can be prepared by proceeding as in thefollowing Reaction Scheme I:

in which R₁, R₂, Y₁, Y₂, Y₃ and Y₄ are as described in the Summary ofthe Invention. Compounds of formula (A) can be prepared by reacting acompound of formula 2 with a compound of formula 3 in the presence of asuitable catalyst (for example, PdCl₂(dppf).CH₂Cl₂ adduct, and thelike), a suitable solvent (for example dioxane and DMF, or the like) anda suitable buffer (for example, Na₂CO₃, or the like). The reactionproceeds at a temperature of about 90° C. to about 140° C. and can takeup to about 1 hour to complete.

Compounds of Formula (A) can also be prepared by proceeding as in thefollowing Reaction Scheme II:

in which R₁, R₂, Y₁, Y₂, Y₃ and Y₄ are as described in the Summary ofthe Invention. Compounds of formula (A) can be prepared by reacting acompound of formula 4 with a compound of formula 3 in the presence of asuitable catalyst (for example, PdCl₂(dppf).CH₂Cl₂ adduct, and thelike), a suitable solvent (for example dioxane and DMF, or the like) anda suitable buffer (for example, Na₂CO₃, or the like). The reactionproceeds at a temperature of about 90° C. to about 140° C. and can takeup to about 1 hour to complete. Descriptions of the synthesis ofspecific examples are described, below.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase.

Alternatively, the salt forms of the compounds of the invention can beprepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula (A) can be made by a process, whichinvolves:

(a) that of reaction schemes I and II; and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer, for example stereoisomer,of a compound of the invention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well-known methods can similarlybe used.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing intermediates and examples that illustrate the preparation ofcompounds of Formula (A) according to the invention.

The following abbreviations may be used herein:

DAST (diethylamino)sulfurtrifluoride DCM Dichloromethane DIADdiisopropylazodicarboxylate DIEA diisopropylethylamine DMADimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethaneDMF N,N-dimethylformamide DPPF 1,1′-bis(diphenylphosphino)ferrocene EDC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc ethylacetate EtOH Ethanol HOAT Hydroxyazabenzotriazole HOBtHydroxybenzotriazole K₂CO₃ Potassium carbonate MeCN Acetonitrile MgSO₄Magnesium sulfate MeOH Methanol Na₂CO₃ sodium carbonate NaCl Sodiumchloride NaHCO₃ sodium bicarbonate NBS N-bromosuccinimide NMPN-methyl-2-pyrrolidone Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh₃)₄Tetrakis(triphenylphospine)palladium(0) Pd(dppf)Cl₂-Dichloro-(1,2-bis(diphenylphosphino)ethan)-Palladium(II)- DCMdichloromothethane adduct RT or rt room temperature TBDMSCltert-butyldimethylsilylchloride TEA Triethylamine THF tetrahydrofuran

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

Mass spectrometric analysis was performed on LCMS instruments: WatersSystem (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: AcuityHSS C18 1.8-micron, 2.1×50 mm; gradient: 5-95% acetonitrile in waterwith 0.05 TFA over a 1.8 min period; flow rate 1.2 mL/min; molecularweight range 200-1500; cone Voltage 20 V; column temperature 50° C.).All masses were reported as those of the protonated parent ions.

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 400 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art in view of the following examples.

INTERMEDIATES Synthesis ofcis-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol

Step 1:

A suspension of zinc (5 equiv) in THF (1 M) was treated withtrimethylsilylchloride (0.25 equiv). The mixture was heated in a 50° C.heating bath (reflux condenser) for 10 min, then ethyl bromoacetate (2.5equiv) was added dropwise. After 25 min, the mixture was cooled to roomtemperature, and the solid was allowed to settle. The supernatant wastransferred via syringe to a flask containing the supernatant aspossible was transferred via syringe to a round-bottom flask containing5-bromo-3-fluoropicolinonitrile (1 equiv), and the resulting mixture wasstirred for 9 h. The reaction mixture diluted with 10% aq. citric acidsolution (2 volumes) and EtOAc (1 volume) and stirred overnight. In themorning, the mixture filtered through celite with the aid of EtOAc andwater. The layers were separated, and the aq. layer was extracted withEtOAc. The combined organic layers were dried over sodium sulfate,filtered, and concentrated. The residue was wet so it was diluted withwater and extracted with DCM (3×). The combined organic extracts weredried over sodium sulfate, filtered, and concentrated. The residue waspurified by silica gel chromatography (0-30% EtOAc/heptane) to giveethyl 3-(5-bromo-3-fluoropyridin-2-yl)-3-oxopropanoate (35.7% yield) asa yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.56 (dd, J=1.71,0.98 Hz, 1H) 7.78 (dd, J=9.66, 1.83 Hz, 1H) 4.15-4.25 (m, 2H) 4.12 (s,2H) 1.19-1.30 (m, 3H). LCMS (m/z) (M+H)=289.9, Rt=1.32 min.

Step 2:

Into a round-bottom flask were charged morpholin-3-one (1 equiv) and DCM(0.65 M). To the mixture at room temperature under nitrogen was addedtriethyloxonium tetrafluoroborate (1.1 equiv). The mixture was agitatedat room temperature overnight. The next morning, the reaction mixturewas quenched by the addition of saturated aq. sodium carbonate solution.The organic layer was separated, dried over sodium sulfate, filtered,and concentrated in vacuo (35° C., 250 mmHg) to afford the crude5-ethoxy-3,6-dihydro-2H-1,4-oxazine (65.3% yield) as a 50% solution inDCM. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.34 (d, J=8.56 Hz, 1H) 7.69(d, J=1.59 Hz, 1H) 7.56 (dd, J=8.56, 1.71 Hz, 1H) 5.00 (s, 2H) 4.42 (q,J=7.09 Hz, 2H) 4.18-4.27 (m, 2H) 4.02-4.11 (m, 2H) 1.41 (t, J=7.15 Hz,3H).

Step 3:

A vial was charged with ethyl3-(5-bromo-3-fluoropyridin-2-yl)-3-oxopropanoate (1 equiv) and5-ethoxy-3,6-dihydro-2H-1,4-oxazine (1.1 equiv), sealed, and heated to115° C. After 3 h, an additional portion of5-ethoxy-3,6-dihydro-2H-1,4-oxazine (1.1 equiv) was added, and themixture was heated overnight. In the morning, the mixture was cooled andconcentrated. The residue was concentrated from EtOH, then taken up inEtOH and heated to boiling for 1 min. The mixture was cooled to roomtemperature then filtered. The collected solid was washed with EtOH(2×), then dried under a flow of N₂ (g) to give ethyl9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(59% yield) as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (d,J=1.83 Hz, 1H) 8.62 (d, J=1.83 Hz, 1H) 4.83 (s, 2H) 4.26 (q, J=7.09 Hz,2H) 4.07-4.21 (m, 4H) 1.27 (t, J=7.15 Hz, 3H). LCMS (m/z) (M+H)=352.9,Rt=0.86 min.

Step 4:

A vial was charged with ethyl9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1 equiv) a 1.4:1 water/AcOH mixture (0.2 M). Sulfuric acid (6.5 equiv)was added, resulting in a solution. The vial was heated to 110° C. for 2h. After cooling to room temperature, the mixture was filtered, and thecollected solid was washed with water (2×), then dried under a flow ofN₂ (g) overnight to give9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid as an off-white solid. LCMS (m/z) (M+H)=324.9, Rt=0.76 min.

Step 5:

9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1 equiv) was suspended in MeOH (0.07 M), and sodium borohydride (4equiv) was carefully added in 3 portions. After stirring for 5 min,p-toluenesulfonic acid monohydrate (0.1 equiv) was added. The mixturewas heated to 65° C. for 2 h, then cooled to room temperature, dilutedwith acetone, and concentrated. The residue was taken up in sat. aq.sodium bicarbonate solution and extracted with EtOAc (3×). The combinedorganic extracts were dried over sodium sulfate, filtered, andconcentrated to give9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(88% yield) as a yellow solid. LCMS (m/z) (M+H)=284.9, Rt=0.90 min.

Step 6:

9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was suspended in 3:2 MeOH/THF (0.1 M). The suspension wascooled to 0° C. and then sodium borohydride (2 equiv) was added in oneportion. After 10 min, the cooling bath was removed. The mixture wasstirred at room temperature for 1.5 h, then saturated. aq. ammoniumchloride solution was added. The volatiles were removed in vacuo. Theresulting mixture was diluted with water and extracted EtOAc (3×). Thecombined organic extracts were dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography on silica gel(0-50% EtOAc/heptane) to give racemiccis-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(71% yield, 90% purity) as a white solid. LCMS (m/z) (M+H)=286.9,Rt=0.65 min.

Synthesis of diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate

Step 1:

A suspension of 3,5-dichloropicolinic acid (1 equiv) in DCM (0.3 M)containing catalytic DMF (5 drops) was treated dropwise with oxalylchloride (1.3 equiv). After 3 h, the mixture was concentrated. Theresidue was concentrated from DCM (1×), then taken up in DCM (0.35 M).The resulting solution was cooled in an ice-water bath for 5 min, thenN,O-dimethylhydroxylamine hydrochloride (1.2 equiv) was added.Triethylamine (2.5 equiv) was added dropwise and a thick mixture formed.The cooling bath was removed, and an additional portion of DCM (0.35 M)was added. After stirring overnight, the mixture was washed with water,washed with 1N aq. HCl, washed with brine, dried over sodium sulfate,filtered, and concentrated. The residual solid was taken up in heptane(some residue remained on the flask), then filtered, washed withheptane, dried under a flow of N₂ (g), then dried under vacuum to give3,5-dichloro-N-methoxy-N-methylpicolinamide (88% yield) as a whitesolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.49 (d, J=1.96 Hz, 1H) 7.80(d, J=1.96 Hz, 1H) 3.58 (s, 3H) 3.41 (s, 3H). LCMS (m/z) (M+H)=253.2,Rt=1.03 min.

Step 2:

A vial was charged with 3,5-dichloro-N-methoxy-N-methylpicolinamide (1equiv) and morpholine (6 equiv). The vial was sealed and heated to 140°C. for 8 h. After the mixture was cooled to room temperature, it wasdiluted with ether and filtered with the aid of ether. The filtrate waswashed with 1N aq. HCl (300 mL), and the aq. layer was extracted withether (2×150 mL). The combined ethereal extracts were dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedby chromatography on silica gel (20-70% EtOAc/heptane) to give5-chloro-N-methoxy-N-methyl-3-morpholinopicolinamide (74.4% yield) as anoily white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24 (d, J=1.96Hz, 1H) 7.36 (d, J=1.59 Hz, 1H) 3.75-3.94 (m, 4H) 3.59 (s, 3H) 3.37 (s,3H) 3.08 (br s, 4H). LCMS (m/z) (M+H)=286.0, Rt=0.92.

Step 3:

5-chloro-N-methoxy-N-methyl-3-morpholinopicolinamide (1 equiv) wascharged in a round-bottom flask, then concentrated from toluene (1×).The residue was dissolved in THF (0.2 M), and the resulting solution wascooled in an ice-water bath for 10 min. A solution of DIBAL-H (1 M inTHF, 2 equiv) was added dropwise over 5 min. After 10 min of stirring,the reaction was quenched by the addition of EtOAc (20 equiv). Themixture was then diluted with 1N aq. HCl, resulting in some bubbling.The mixture was stirred for 5 min, then extracted with EtOAc (3×). Theaq. layer was neutralized with sat. bicarb solution and extracted withDCM (2×). An emulsion formed, so more DCM was added, and the wholemixture was stirred vigorously with sat. aq. Rochelle's salt solutionovernight. The next morning, the mixture was extracted with DCM (3×).The combined organic extracts were dried over sodium sulfate, filtered,and concentrated to give (5-chloro-3-morpholinopyridin-2-yl)methanol(90% yield) as a light red solid. LCMS (m/z) (M+H)=229.1, Rt=0.71 min.

Step 4:

A solution of (5-chloro-3-morpholinopyridin-2-yl)methanol (1 equiv) inDCM (0.2 M) cooled in an ice-water bath was treated with Dess-Martinperiodinane (1.1 equiv). After 30 min of stirring, an additional portionof Dess-Martin periodinane (0.3 equiv) was added, and the cooling bathwas removed. After stirring at room temperature for 3 h, the mixture wasrecooled in an ice-water bath for 5 min, then an additional portion ofDess-Martin (0.15 equiv) was added. After another 10 min, a sat. aq.sodium bicarbonate solution was carefully added. The mixture was stirredfor 1 h, then was further diluted with sat. aq. sodium thiosulfatesolution and extracted with DCM (5×). The combined organic extracts weredried over sodium sulfate, filtered, and concentrated. The residue waspurified by chromatography on silica gel (0-50% EtOAc/heptane) to give5-chloro-3-morpholinopicolinaldehyde (84% yield) as a yellow oil: ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 10.09 (d, J=0.73 Hz, 1H) 8.35 (d, J=1.96Hz, 1H) 7.39 (d, J=1.96 Hz, 1H) 3.91-4.00 (m, 4H) 3.14-3.22 (m, 4H).LCMS (m/z) (M+H)=227.0, Rt=1.03 min.

Step 5:

A flask was charged with 5-chloro-3-morpholinopicolinaldehyde (1 equiv),toluene (0.2 M), diethyl malonate (1.1 equiv), and acetic anhydride (1.2equiv) to give a solution. Indium(III) chloride (0.065 equiv) was added,and the flask was heated to 80° C. for 5 h. The mixture was cooled, thenpartitioned between saturated aq. sodium bicarbonate solution and EtOAc.The aq. layer was extracted with EtOAc (2×), and the combined organicextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated. The residue was purified by chromatography on silicagel (25-75% EtOAc/heptane) to give diethyl2-((5-chloro-3-morpholinopyridin-2-yl)methylene)malonate (90% yield) asa yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24 (d, J=1.96 Hz,1H) 7.94 (s, 1H) 7.34 (d, J=2.20 Hz, 1H) 4.36 (dq, J=14.21, 7.16 Hz, 4H)3.86-3.99 (m, 4H) 2.96-3.10 (m, 4H) 2.07 (s, 1H) 1.28-1.40 (m, 2H) 1.36(d, J=7.83 Hz, 4H). LCMS (m/z) (M+H)=369.0, Rt=1.49 min.

Step 6:

A solution of diethyl2-((5-chloro-3-morpholinopyridin-2-yl)methylene)malonate (1 equiv) inacetonitrile (0.1 M) was treated with gadolinium(III)trifluoromethanesulfonate (0.1 equiv). The mixture was heated to refluxfor 6 h, then was cooled to room temperature. The mixture wasconcentrated, and the residue was dissolved in toluene (0.1 M). Zincchloride (2 equiv) was added, and the resulting mixture was heated toreflux overnight. The mixture was then cooled, diluted with saturatedaq. bicarbonate solution, EtOAc, and water. The layers were separated,and the aq. layer was extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography on silica gel(25-75% EtOAc/heptane) to give diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate(89% yield) as a light-yellow oil. LCMS (m/z) (M+H)=369.1, Rt=1.32 min.

Synthesis of trans- and cis-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate

A round-bottom flask was charged with diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate(1 equiv), LiCl (2 equiv), DMSO (0.5 M), and water (2 equiv). The flaskwas fitted with a reflux condenser and heated to 180° C. for 6 h, andthe mixture was cooled to room temperature overnight. In the morning,the mixture was diluted with water and a small amount of brine, thenextracted with EtOAc (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel (0-50% EtOAc/heptane). The first elutingspot was collected to give trans-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(69.0% yield); LCMS (m/z) (M+H) 297.0; Rt.=1.08 min. The second elutingspot was collected to give cis-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(15.91% yield). LCMS (m/z) (M+H) 297.0; Rt.=0.93 min.

Synthesis oftrans-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol

A flask was charged with trans-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1 equiv) and THF (0.2 M) to give a clear, yellow solution. The flaskwas cooled in an ice-water bath for 5 min, then lithium aluminum hydride(1M in THF, 1.1 equiv) was added dropwise. After 15 min, sodium sulfatedecahydrate (2 equiv) was added in a single portion, then the coolingbath was removed. After stirring for 20 min at room temperature, themixture was diluted with EtOAc and filtered. The filter pad was washedwith EtOAc (2×) and DCM (1×). The filtrate was concentrated to givetrans-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol(96% yield) as an off-white solid. LCMS (m/z) (M+H)=255.0, Rt.=0.64 min.

Synthesis of 1:1trans-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanolandcis-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol

Step 1:

A vial was charged with diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate(1 equiv) and 1.4:1 water-AcOH. Sulfuric acid (6.5 equiv) was added,resulting in a solution. The vial was heated to 110° C. for 3 h, then anadditional portion of sulfuric acid (6.5 equiv) was added. The vial washeated to 130° C. for 4 h, then cooled to room temperature. The mixturewas diluted with water (1 volume), extracted with DCM (4×). The aq.layer was then concentrated in vacuo. The residue was taken up inmethanol, and the mixture was filtered. The collected solid was washedwith MeOH (4×). The filtrate was concentrated. The residue was treatedwith a small amount of MeOH, then diluted with DCM. The mixture wasfiltered, and the filtrate was again concentrated to give9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (96% yield, 80% purity) as a 1:1 mixture of cis and transdiastereomers. The material was used directly in the next step.

Step 2:

9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1:1 cis/trans, 1 equiv) was suspended in THF (4.5 mL), thenlithium aluminum hydride (1M in THF, 3 equiv) was added dropwise. Theresulting mixture was stirred overnight. In the morning, the mixture wasquenched by the slow addition of sodium sulfate decahydrate (3 equiv).After stirring for 40 min, the mixture was filtered through celite withthe aid of THF. The filtrate was concentrated, and the residue waspurified by chromatography on silica gel (0-10% MeOH/DCM, then 20%MeOH/DCM) to give(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol(44% yield) as a 1:1 mixture of cis and trans diastereomers. LCMS (m/z)(M+H) 255.0; Rt.=0.58, 0.64 mins.

Synthesis of9-bromo-1,2,4,4a-tetrahydropyrido[2′,3′:5,6]pyrazino[2,1-c][1,4]oxazin-5(6H)-one

Step 1:

Carbonyldiimidazole (1.5 equiv) was added to a solution of4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1 equiv) in 3:1DCM/DMF (0.8 M) resulting in bubbling. The resulting mixture was stirredovernight. In the morning, DMF (ca. 1 volume),3,5-dibromopyridin-2-amine (2 equiv), N,N-diisopropylethylamine (2equiv), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 equiv) were added. Areflux condenser was attached, and the flask was heated to 90° C. for 1h. The mixture was then cooled, diluted with water, and extracted withEtOAc (3×). The combined organic extracts were dried over sodiumsulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel (0-40% EtOAc/heptane) to give tert-butyl3-((3,5-dibromopyridin-2-yl)carbamoyl)morpholine-4-carboxylate (79%yield) as an off-white foam. LCMS (m/z) (M+H)=465.9, Rt=1.33 min.

Step 2:

A flask was charged with tert-butyl3-((3,5-dibromopyridin-2-yl)carbamoyl)morpholine-4-carboxylate (1equiv), 2:1 DCM/TFA (0.12 M) (2 pm). The mixture was stirred for 30 min,then concentrated. The residue was concentrated from ether. The residuewas diluted with saturated aq. sodium bicarbonate solution and extractedwith DCM (3×). The combined organic extracts were dried over sodiumsulfate, filtered, and concentrated to giveN-(3,5-dibromopyridin-2-yl)morpholine-3-carboxamide (75% yield) as awhite solid. LCMS (m/z) (M+H)=365.8, Rt=0.67 min.

Step 3:

A vial was charged with xantphos (0.3 equiv), palladium acetate (0.1equiv), 1,4-dioxane (0.07 M relative to starting material), and water(0.4 equiv). The vial was sealed and heated to 110° C. for 5 min to givea dark maroon solution. To the cooled solution was then added to a vialcontaining N-(3,5-dibromopyridin-2-yl)morpholine-3-carboxamide (1equiv), potassium phosphate (3 equiv, freshly ground), 4-A molecularsieves (50 mg/mL). The vial was sealed and heated to 140° C. for 2 h ina microwave reactor. The mixture was cooled to room temperature, thenfiltered through celite with the aid of THF. The filtrate wasconcentrated, and the residue was taken up in 10% MeOH/DCM to give asuspension. The suspension was filtered, and the collected solid waswashed with DCM (2×), then dried under a flow of N₂ (g) to give9-bromo-1,2,4,4a-tetrahydropyrido[2′,3′:5,6]pyrazino[2,1-c][1,4]oxazin-5(6H)-one(13%) of an off-white solid that was 90% pure as assessed by LCMS. LCMS(m/z) (M+H)=283.9, Rt=1.03 min.

Synthesis of9-bromo-6-ethyl-1,2,4,4a-tetrahydropyrido[2′,3′:5,6]pyrazino[2,1-c][1,4]oxazin-5(6H)-one

A flask was charged with sodium hydride (60% in mineral oil) (2 equiv)and DMF (0.1 M).9-Bromo-1,2,4,4a-tetrahydropyrido[2′,3′:5,6]pyrazino[2,1-c][1,4]oxazin-5(6H)-one(1 equiv) was added. After 25 min, iodoethane (3 equiv) was added. Afteranother 10 min of stirring, the mixture was quenched with saturated aq.ammonium chloride solution and water, then extracted with EtOAc (3×).The combined organic extracts were dried over sodium sulfate, filtered,and concentrated. The residue was purified by chromatography on silicagel (0-30% EtOAc/heptane) to give9-bromo-6-ethyl-1,2,4,4a-tetrahydropyrido[2′,3′:5,6]pyrazino[2,1-c][1,4]oxazin-5(6H)-one(89% yield) as a white solid. LCMS (m/z) (M+H) 313.9, Rt=1.42 min.

Synthesis of2-chloro-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-one

A vial was charged with 4-bromo-6-chloropyridazin-3-amine (1 equiv),morpholine-3-carboxylic acid (1.3 equiv), copper(I) iodide (0.1 equiv),and cesium carbonate (2 equiv). The vial was flushed with N₂ (g), thenDMSO (0.65 M) was added. The vial was sealed and heated to 130° C. for 3h. The mixture was cooled, diluted with saturated aq. ammonium chloridesolution, extracted with EtOAc (3×), and extracted with DCM (3×). Thecombined organic extracts were dried over sodium sulfate, filtered, andconcentrated. The residue was concentrated from DCM, then taken up inDCM and filtered. The collected solid was washed with DCM (3×) thendried under vacuum to give2-chloro-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-one(23.22% yield) as an off-white solid, with 92% purity as assessed byLCMS and NMR. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H) 6.99-7.05(m, 1H) 4.12-4.25 (m, 2H) 3.93 (dd, J=11.62, 3.55 Hz, 1H) 3.75 (dd,J=12.96, 1.96 Hz, 1H) 3.36-3.58 (m, 2H) 2.93-3.02 (m, 1H). LCMS (m/z)(M+H)=214.0, Rt=0.66 min (basic polar method).

Synthesis of2-chloro-5-ethyl-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-oneand2-chloro-5,6a-diethyl-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-one

To an opaque mixture of2-chloro-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-one(1 equiv) and DMF (0.2 M) was added sodium hydride (60% in mineral oil,2 equiv) in one portion. The mixture was stirred for 50 min, theniodoethane (3 equiv) was added dropwise. The mixture was stirred 30 min,quenched with saturated aq. ammonium chloride solution and water, andextracted with EtOAc (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel (0-50% EtOAc/heptane) to give2-chloro-5,6a-diethyl-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-one(first eluting peak, 28.2% yield), LCMS (m/z) (M+H)=297.0, Rt=1.15 minand2-chloro-5-ethyl-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrazino[2,1-c][1,4]oxazin-6(5H)-one(second eluting peak, 31.7% yield), LCMS (m/z) (M+H)=269.0, Rt=0.97 min.

Synthesis of 5-chloro-3-fluoro-2-nitropyridine

A round-bottom flask was charged with 3,5-dichloropyridin-2-amine (1equiv), sulfuric acid (0.5 M) to give a solution. Potassium persulfate(5 equiv) was added in two portions over 10 min. After stirring for 20min, a substantial exotherm and gas evolution was observed. Theresulting mixture was stirred overnight. The next morning the mixturewas poured into crushed ice with the aid of water, then the aq. mixturewas treated with solid sodium carbonate until it reached pH 8-10. Theaq. mixture was extracted with DCM (3×), and the combined organicextracts were dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by chromatography on silica gel (0-50%EtOAc/heptane) to give 5-chloro-3-fluoro-2-nitropyridine (31.6% yield)as an off-white solid. LCMS (m/z) (M+H)=176.9, Rt=1.03 min.

Synthesis of10-chloro-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(7H)-one

A vial was charged with 5-chloro-3-fluoro-2-nitropyridine (1 equiv),methyl 2-(morpholin-3-yl)acetate hydrochloride (1.1 equiv), DMF (0.4 M),and triethylamine (3 equiv). The vial was sealed and heated to 80° C.for 7 h. The mixture was cooled, then diluted with 1N aq. HCl andextracted with EtOAc (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated. The residue was dissolved inacetic acid (0.2 M). Iron (10 equiv) was added, and the resultingmixture was heated to 110° C. overnight. The mixture was cooled to roomtemperature, diluted with EtOAc and filtered through celite. The filterpad was washed successively with EtOAc, DCM, and 20% MeOH/DCM. Thecombined filtrate was concentrated. The residue was suspended betweensat. aq. sodium bicarbonate and EtOAc. The layers were separated, andthe aq. layer was extracted with EtOAc (4×). The combined organicextracts were dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by chromatography on silica gel (40-90%EtOAc/heptane) to give10-chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(54% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (s,1H) 8.05 (d, J=2.20 Hz, 1H) 7.57 (d, J=2.20 Hz, 1H) 3.75-3.88 (m, 2H)3.36-3.53 (m, 3H) 3.16-3.29 (m, 1H) 2.96 (br d, J=11.13 Hz, 1H)2.60-2.69 (m, 1H) 2.02 (d, J=13.69 Hz, 1H). LCMS (m/z) (M+H)=254.0,Rt=0.89 min.

Synthesis of10-chloro-7-ethyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(7H)-one

A round-bottom flask was charged with10-chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(1 equiv) and DMF (0.15 M) to give a clear, colorless solution. Sodiumhydride (60% in mineral oil, 1.3 equiv) was added in one portion. Themixture was stirred for 35 min, then iodoethane (1.2 equiv) was added.The mixture was stirred for a n additional 20 min, quenched with sat.aq. ammonium chloride solution, and extracted with EtOAc (3×). Thecombined organic extracts were concentrated. The residue was purified bychromatography on silica gel (0-40% EtOAc/heptane) to give10-chloro-7-ethyl-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(quantitative yield) as an off-white solid. LCMS (m/z) (M+H)=282.1,Rt=1.19 min.

Synthesis of (4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)methanol

A vial was charged with 2,3,5-trichloropyridine (1 equiv),morpholin-3-ylmethanol (1 equiv), DMF (1 M), and triethylamine (3equiv). The resulting solution was heated to 90° C. for 8 h, then wascooled to room temperature. The cooled mixture was diluted withsaturated. aq. ammonium chloride solution and water, then extracted withEtOAc (4×). The combined organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue was takenup in ether and stirred overnight. In the morning, the mixture wasfiltered, and the collected solid was washed with ether (2×), then driedunder a flow of N₂ (g) to give(4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)methanol (51.9% yield) asa tan solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (s, 1H) 4.53-4.91 (m,1H) 4.04-4.24 (m, 1H) 3.73-3.92 (m, 3H) 3.44-3.70 (m, 4H) 3.16 (br d,J=11.49 Hz, 1H). LCMS (m/z) (M+H)=264.2, Rt=0.79 min.

Synthesis of2-chloro-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine

Sodium hydride (60% in mineral oil, 1.5 equiv) was added to a solutionof (4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)methanol (1 equiv) inDMF (0.125 M). The resulting mixture was stirred for 20 min, dilutedwith saturated. aq. ammonium chloride solution and water, and extractedwith EtOAc (3×). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated to give2-chloro-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine(quantitative yield) as an oil containing ca. 45 wt % of DMF. Thematerial was used directly. LCMS (m/z) (M+H)=228.1, Rt=0.66 min.

Synthesis of2-chloro-6,6-dimethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine

Step 1:

A suspension of (4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)methanol(1 equiv) in a 3:2:2 mixture of water:acetonitrile:ethyl acetate wastreated in sequence with sodium periodate (4 equiv) and ruthenium(III)chloride hydrate (0.1 equiv) were added in sequence, and the resultingmixture was stirred vigorously for 2 h. The reaction mixture wasquenched by the addition of EtOH, stirred for 5 min, then diluted withwater and extracted with EtOAc (4×). The combined organic extracts weredried over sodium sulfate, filtered, and concentrated. The residue wastaken up in 1:1 MeOH/toluene (3 mL). The resulting solution was treateddropwise with TMS-diazomethane (2M in hexanes, 2 equiv). After 2 h, thereaction was quenched with acetic acid and concentrated. The residue waspurified by chromatography on silica gel (0-50% EtOAc/heptane) to givemethyl 4-(3,6-dichloropyridazin-4-yl)morpholine-3-carboxylate (82.1 mg,0.281 mmol, 52.1% yield) as a light-yellow oil. LCMS (m/z) (M+H)=292.0,Rt=1.05 min.

Step 2:

A vial charged with methyl4-(3,6-dichloropyridazin-4-yl)morpholine-3-carboxylate (1 equiv) and THF(0.1 M) to give a solution. Methylmagnesium bromide (3M in ether, 10equiv) was added dropwise. The mixture was stirred for 30 min, then wasquenched by the careful addition of saturated aq. ammonium chloridesolution. The mixture was diluted with water and extracted with EtOAc(3×). The combined organic extracts were dried over sodium sulfate,filtered, and concentrated to give crude2-(4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)propan-2-ol as a brownoil. This material was dissolved in DMF (0.1 M) and treated with sodiumhydride (60% in mineral oil, 1.5 equiv) in one portion. The mixture wasstirred for 4 h at room temperature, then was diluted with saturated aq.ammonium chloride and water and extracted with EtOAc (3×). The combinedorganic extracts were dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography on silica gel(50-100% EtOAc/heptane) to give2-chloro-6,6-dimethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine(82% yield) as a yellow oil. LCMS (m/z) (M+H)=256.0, Rt=0.85 min.

Synthesis of9-chloro-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol

Step 1:

9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was dissolved in THF (0.2 M) and the partial solution wascooled in a dry ice-acetone bath. Lithium diisopropylamide (2M inTHF/heptane/ethylbenzene, 1.1 equiv) was added dropwise. The flask wastransferred to an ice-water bath for 40 min, then re-cooled in a dryice-acetone bath. A solution of N-fluorobenzenesulfonimide (1.3 equiv)in THF was added dropwise. The mixture was stirred for 2 h, then theflask was warmed to −40° C. for 30 min, then warmed to room temperature.The reaction mixture was diluted with saturated aq. sodium bicarbonatesolution and extracted with EtOAc (3×). The combined organic extractswere dried over sodium sulfate, filtered, and concentrated. The residuewas purified by chromatography on silica gel (10-60% EtOAc/heptane) togive9-chloro-5-fluoro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(14.73% yield) as a yellow solid. LCMS indicated an 8:1 mixture ofdiastereomers. LCMS (m/z) (M+H)=257.3, Rt=0.88 min.

Step 2:

9-chloro-5-fluoro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was dissolved in MeOH (0.1 M). The resulting solution wascooled in an ice-water bath and NaBH₄ (6.49 mg, 0.171 mmol) was added.The resulting mixture was stirred for 45 min, then the reaction wasquenched by the addition of acetone and saturated aq. ammonium chloridesolution. The mixture was partitioned between EtOAc and water, and theaqueous phase was separated and washed with EtOAc (2×). The combinedorganics were dried over sodium sulfate, filtered and concentrated togive9-chloro-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olas a light yellow solid. LCMS (m/z) (M+H)=259.2, Rt=0.85 min.

Synthesis of9-bromo-6,6-difluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine

A round-bottom flask was charged with9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv), DCM (0.1 M), Deoxo-Fluor (3 equiv) and ethanol (0.1 equiv).The resulting mixture was stirred for 3 d, then diluted with saturated.aq. sodium bicarbonate solution and extracted with DCM (3×). Thecombined organic extracts were dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography on silica gel(40-90% EtOAc/heptane) to give9-bromo-6,6-difluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(27.5% yield) as an off-white solid (top spot) as well as recoveredstarting material (35-40%). LCMS (m/z) (M+H)=304.9, Rt=1.24 min.

Synthesis of(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5-diyl)dimethanol

Diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate(1 equiv) was dissolved in DCM (0.2 M) and the reaction was cooled to−78° C. DIBAL-H (1 M in THF, 10 equiv) was added slowly and the reactionwas stirred at −78° C. for 5 minutes. The reaction was taken out of theacetone/dry ice bath and then stirred at room temperature for 45 minutesbefore quenching with the addition of saturated Rochelle's saltsolution. After gas evolution had stopped, DCM was added and thereaction was stirred at room temperature overnight. The layers wereseparated and the aqueous layer was washed three times with DCM, thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(0-20% MeOH/DCM) and the resulting material was dried under high vacuumfor 45 minutes to give(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5-diyl)dimethanol(40% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d,J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 4.68 (br s, 1H), 4.57 (br s, 1H),3.95 (dd, J=11.2, 2.8 Hz, 1H), 3.85 (d, J=12.3 Hz, 1H), 3.77 (dd,J=11.5, 3.1 Hz, 1H), 3.42 (t, J=11.0 Hz, 4H), 3.25 (dd, J=10.8, 2.9 Hz,2H), 2.93 (td, J=12.6, 3.5 Hz, 1H), 2.61 (m, 3H). LCMS (m/z)(M+H)=285.2, Rt=0.55 min.

Synthesis of9-chloro-2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a][1,5]naphthyridine-5,3′-oxetane]

(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5-diyl)dimethanol(1 equiv) was dissolved in THF (0.15 M) and the solution was cooled to0° C. Then, butyllithium (2.5 M in hexanes, 1.1 equiv) was addeddropwise and stirred for 20 minutes. A solution of p-toluenesulfonylchloride (1 equiv) in THF was added and the mixture was stirred at 0° C.for 1 hour. Butyllithium (2.5 M in hexanes, 1.1 equiv) was added and thereaction was heated overnight at 60° C. The reaction was allowed to coolto room temperature, quenched with the addition of water and partitionedbetween EtOAc and water. The aqueous phase was washed with EtOAc, thecombined organics were washed with brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel (0-10% MeOH/DCM) and theresulting material was dried under high vacuum overnight to give9-chloro-2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a][1,5]naphthyridine-5,3′-oxetane](43.2% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (d,J=2.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 4.54 (d, J=6.3 Hz, 1H), 4.49 (d,J=6.4 Hz, 1H), 4.26 (dd, J=12.8, 6.4 Hz, 2H), 4.17 (dd, J=11.2, 3.0 Hz,1H), 3.84 (m, 2H), 3.61 (t, J=11.0 Hz, 1H), 3.52 (td, J=11.6, 2.5 Hz,1H), 3.45 (dd, J=10.8, 3.1 Hz, 1H), 3.11 (s, 2H), 2.95 (td, J=12.4, 3.4Hz, 1H). LCMS (m/z) (M+H)=267.3, Rt=0.77 min.

Synthesis of9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one

Step 1:

Ethyl9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1 equiv) was suspended in water and acetic acid (0.2 M. Ratio 1:1.4).Sulfuric acid (6.5 equiv) was added to give a solution, which was heatedat 110° C. for 3.5 hours. As the reaction progressed, a solidprecipitated out of solution. The reaction was cooled down to roomtemperature, and then cooled further in an ice bath for 10 minutes. Theprecipitate was filtered off, the solid was washed with water and driedunder a flow of N₂ over the weekend to give9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (80% yield) as a tan solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.00(d, J=1.9 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H), 5.38 (s, 2H), 4.39 (t, J=5.4Hz, 2H), 4.16 (t, J=5.4 Hz, 2H). Singal for carboxylic acid proton isn'tobserved. LCMS (m/z) (M+H)=281.2, Rt=0.72 min.

Step 2:

9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1 equiv) was suspended in MeOH (0.1 M) and then sodium borohydride(3.5 equiv) was added portion-wise. After complete addition,p-toluenesulfonic acid monohydrate (0.1 equiv) was added and thereaction was heated at 70° C. for 1 hour. The reaction was quenched bythe addition of acetone and then concentrated. The residue was dilutedwith EtOAc and sonicated, water was added and the organic layer wasseparated and dried over magnesium sulfate, filtered and concentrated.The resulting solid was dried under high vacuum for 30 minutes to give9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(80% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d,J=1.9 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 4.02 (dd, J=11.7, 3.7 Hz, 1H),3.93 (dd, J=11.7, 3.1 Hz, 1H), 3.82 (m, 1H), 3.63 (td, J=11.9, 2.8 Hz,1H), 3.54 (m, 1H), 3.36 (t, J=11.2 Hz, 1H), 2.82 (td, J=12.2, 3.8 Hz,1H), 2.59 (s, 1H), 2.56 (d, J=2.1 Hz, 1H). LCMS (m/z) (M+H)=239.2,Rt=0.85 min.

Synthesis ofcis-9-chloro-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol

Step 1:

9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was dissolved in THF (0.2 M) and the solution was cooled to 0°C. and sodium hydride (60% in mineral oil, 2.5 equiv) was added. Thereaction was stirred at 0° C. for 30 minutes, iodomethane (2.5 equiv)was added and the reaction was stirred at room temperature for 45minutes. The reaction was quenched by the addition of acetone andsaturated ammonium chloride solution. The reaction was partitionedbetween EtOAc and water, the aqueous phase was separated and washed withEtOAc. The combined organics were washed with brine, dried overmagnesium sulfate, concentrated and dried under high vacuum overnight togive9-chloro-5,5-dimethyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-oneas a green film, which was used in the next step without furtherpurification. LCMS (m/z) (M+H)=267.2, Rt=1.03 min.

Step 2:

9-chloro-5,5-dimethyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was dissolved in MeOH (0.2 M) and cooled in an ice bath,sodium borohydride (2 equiv) was added. After stirring at 0° C. for 5minutes, the reaction was taken out of the ice bath and stirred at roomtemperature for 45 minutes. The reaction was quenched by the addition ofacetone and saturated ammonium chloride solution. The reaction waspartitioned between EtOAc and water, the aqueous phase was separated andwashed with EtOAc. The combined organics were washed with brine, driedover magnesium sulfate and concentrated. The residue was purified bychromatography on silica gel (0-50% EtOAc/heptane) and the resultingmaterial was dried under high vacuum for 1 hour to givecis-9-chloro-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(61.4% yield) as a pale yellow film. LCMS (m/z) (M+H)=269.2, Rt=0.81min.

Synthesis ofcis-9-chloro-5,5-difluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol

Step 1:

9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was dissolved in THF (0.15 M), sodium hydride (60% in mineraloil, 3 equiv) was added and the reaction was stirred at room temperaturefor 20 minutes. N-fluorobenzenesulfonimide (2 equiv) was added and thereaction was stirred at room temperature for 1 hour. The reaction wasquenched by the addition of saturated ammonium chloride solution and waspartitioned between EtOAc and water. The aqueous phase was washed withEtOAc, the combined organics were washed with saturated sodiumbicarbonate solution, brine, dried over magnesium sulfate, filtered andconcentrated. The resulting material was transferred to a pre-tared vialwith DCM/MeOH and the solvent was concentrated and dried under highvacuum overnight to give9-chloro-5,5-difluoro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-oneas a brown oil, which was used in the next step without furtherpurification. LCMS (m/z) (M+H)=275.2, Rt=1.07 min.

Step 2:

9-chloro-5,5-difluoro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was dissolved in MeOH (0.2 M) and cooled in an ice bath,sodium borohydride (2 equiv) was added. After ten minutes stirring at 0°C., the reaction was taken out of the ice bath and stirred at roomtemperature for 1.5 hours. The reaction was quenched by the addition ofacetone and saturated ammonium chloride solution. The reaction waspartitioned between EtOAc and water, the aqueous phase was separated andwashed with EtOAc. The combined organics were washed with brine, driedover magnesium sulfate and concentrated. The residue was purified bychromatography on silica gel (0-50% EtOAc/heptane) and the resultingmaterial was dried under high vacuum for 30 minutes to givecis-9-chloro-5,5-difluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(57% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d,J=1.7 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 6.24 (br s, 1H), 4.89 (dd,J=19.6, 8.6 Hz, 1H), 4.06 (dd, J=11.0, 2.8 Hz, 1H), 3.94 (dd, J=11.6,3.1 Hz, 1H), 3.80 (m, 2H), 3.65 (t, J=10.9 Hz, 1H), 3.54 (td, J=11.9,2.6 Hz, 1H), 2.88 (td, J=12.1, 3.4 Hz, 1H). LCMS (m/z) (M+H)=277.0,Rt=0.96 min.

Synthesis ofcis-9-chloro-6-(trifluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol

9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv) was suspended in THF (0.2 M). Trimethyl(trifluoromethyl)silane(2M in THF) (2 equiv) was added, followed by cesium fluoride (0.1equiv). The reaction was stirred at room temperature for 1.5 hours. 1MHCl (1 ml) was added and the reaction was stirred at room temperatureovernight. The reaction was partitioned between EtOAc and water, theorganic phase was washed with brine, dried over magnesium sulfate,filtered and concentrated. The residue was purified by chromatography onsilica gel (0-30% EtOAc/heptane) and the resulting material was driedunder high vacuum for 45 minutes to givecis-9-chloro-6-(trifluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olacid (61% yield) as a pale pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.97 (d, J=1.8 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 6.48 (s, 1H), 3.94 (d,J=11.4 Hz, 2H), 3.85 (d, J=11.5 Hz, 1H), 3.52 (td, J=11.7, 2.6 Hz, 1H),3.20 (m, 2H), 2.81 (td, J=12.3, 3.5 Hz, 1H), 2.36 (dd, J=14.2, 2.7 Hz,1H), 1.74 (t, J=12.8 Hz, 1H). LCMS (m/z) (M+H)=309.0, Rt=1.33 min.

Synthesis of9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-amine

Step 1:

cis-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olwas dissolved in toluene (0.2 M) and cooled to 0° C. Diphenylphosphorylazide (1.5 equiv) and 1,8-Diazabicycloundec-7-ene (1.2 equiv) were addedand the reaction was taken out of the ice bath and stirred overnight atroom temperature. The reaction was concentrated under reduced pressureand partitioned between EtOAc and saturated sodium bicarbonate solution.The aqueous phase was washed with EtOAc, the combined organics werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. The resulting material was dried under high vacuum for 30minutes to give6-azido-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridineas a brown oil, which was used in the next step without purification.LCMS (m/z) (M+H)=312.2, Rt=1.33 min.

Step 2:

6-azido-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(1 equiv) was dissolved in THF/H₂O (0.2 M. Ratio 10:1).Triphenylphosphine was added and the reaction was stirred at roomtemperature overnight. The reaction was concentrated under reducedpressure, toluene was added and then concentrated under reducedpressure. Et₂O was added and the precipitate was removed by filtration.The resulting material was purified by chromatography on silica gel(0-20% MeOH/DCM) and the resulting material was dried under high vacuumfor 30 minutes to give9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-amine(32% yield) as a brown oil. LCMS (m/z) (M+H)=284.1, Rt=0.69 min.

Synthesis of9-chloro-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxamide

Step 1:

Diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate(1 equiv) was suspended in water and acetic acid (0.2 M. Ratio 1:1.4),sulfuric acid (10 equiv) was added resulting in a solution. The reactionwas heated in a sealed vial for 6 hours and allowed to cool to roomtemperature overnight. The reaction was concentrated and the residue wastaken up in MeOH, the solvent was concentrated under reduced pressureand the residue was partitioned between DCM and water, the aqueous layerwas washed with DCM three times. The combined organics were washed withbrine, dried over magnesium sulfate and concentrated. The resultingmaterial was dried under high vacuum for 1 hour to give methyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylateas a brown oil, which was taken forward to the next step without furtherpurification. LCMS (m/z) (M+H)=283.3, Rt=0.80 and 0.94 min. LCMSindicates approximately 1:1 mixture of diastereomers.

Step 2:

Methyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1 equiv) was dissolved in THF/MeOH (0.2 M. Ratio 1:1). Lithiumhydroxide (1 M aqueous solution, 2.5 equiv) was added and the reactionwas stirred at room temperature for 1.5 hours. The reaction wasconcentrated and partitioned between EtOAc and water. The aqueous phasewas acidified to pH 2-3 using 1M HCl, then partitioned between EtOAc andwater. The organic phase was separated and the aqueous phase was washedwith EtOAc, the combined organics were washed with brine and dried overmagnesium sulfate. The solvent was concentrated and the resultingmaterial was dried under high vacuum overnight to give9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid as a cream solid, which was taken forward to the next step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.77 (br s, 1H),7.83 (d, J=1.9 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H), 3.87 (q, J=11.0, 9.7 Hz,2H), 3.76 (d, J=12.4 Hz, 1H), 3.49 (m, 2H), 3.24 (m, 1H), 2.94 (m, 3H),2.63 (m, 1H). LCMS (m/z) (M+H)=269.1, Rt=0.76 min.

Step 3:

9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1 equiv) was suspended in DMF (0.2 M). EDC.HCl (1.2 equiv) andHOAt (1.2 equiv) was added, followed by methylamine (2.0 M in THF, 3equiv) to give a solution. The reaction was stirred at room temperaturefor 2 hours, another portion of methylamine (2.0 M in THF, 3 equiv) wasadded and the reaction was stirred at room temperature for 1 hour. Thereaction was partitioned between EtOAc and water, the organic phase waswashed three times with water. The combined organics were then washedwith brine, dried over magnesium sulfate, filtered and concentrated togive a solid. The solid was dried under high vacuum over the weekend togivetrans-9-chloro-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxamide(75% yield) as a cream solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (d,J=4.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 3.92 (d,J=8.1 Hz, 1H), 3.74 (m, 2H), 3.50 (td, J=12.0, 3.0 Hz, 1H), 3.15 (m,2H), 2.94 (m, 1H), 2.83 (m, 3H), 2.62 (d, J=4.6 Hz, 3H). LCMS (m/z)(M+H)=282.2, Rt=0.52 and 0.65 min. LCMS indicates presence of twodiastereomers, 85% major at 0.65 min and 15% minor at 0.52 mins.

9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one

Step 1:

3,5-dichloropicolinic acid (1.0 equiv.) was dissolved in 5:1 toluene:methanol (0.5 M) and then TMS-diazomethane (1.2 equiv.) was addeddropwise. The reaction mixture was agitated at room temperature for 1 hand quenched by addition of glacial acetic acid drop-wise until theeffervescence had subsided and concentrated in vacuo and the residue wastriturated with heptane and the dark brown precipitate methyl3,5-dichloropicolinate was collected by filtration. LCMS (m/z)(M+H)=205.9, Rt=1.18 min.

Step 2:

Into a flask was charged methyl 3,5-dichloropicolinate (1.0 equiv.) andEtOAc (0.5M) and the mixture was cooled in an ice-bath. To the mixturewas added potassium tert-pentoxide (2.0 M in THF) (1.2 equiv.) over 10min during which the mixture turned turbid orange and the mixture liftedfrom the cooling bath. After 10 min, LCMS indicated formation of desiredproduct as major species along with hydrolyzed SM (minor species). Thereaction mixture was quenched by addition of sat'd NH₄Cl and extractedwith EtOAc. The organic layer was separated and dried (MgSO4), filteredand concentrated in vacuo and the residue purified by flashchromatography (0-30% EtOAc/heptane) to afford the desired product ethyl3-(3,5-dichloropyridin-2-yl)-3-oxopropanoate as an orange oil. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.46-8.68 (m, 1H) 7.72-8.06 (m, 1H) 4.19(q, J=7.13 Hz, 2H) 4.13 (s, 2H) 1.25 (t, J=7.09 Hz, 3H); LCMS (m/z)(M+H)=263.8, Rt=1.08 min.

Step 3:

ethyl 3-(3,5-dichloropyridin-2-yl)-3-oxopropanoate (1.0 equiv.) and5-ethoxy-3,6-dihydro-2H-1,4-oxazine (2.0 equiv.) were combined in a 40mL vial and heated at 120° C. for 96 h. The reaction mixture was cooledto room temperature and directly loaded onto 300 gram silica cartridgeand purified by flash chromatography (0-100% EtOAc) affording product(E)-ethyl3-(3,5-dichloropyridin-2-yl)-2-(morpholin-3-ylidene)-3-oxopropanoate in71% isolated yield. LCMS (m/z) (M+H)=345.0, Rt=1.28 min.

Step 4:

Into a MW vial were charged product (E)-ethyl3-(3,5-dichloropyridin-2-yl)-2-(morpholin-3-ylidene)-3-oxopropanoate(1.0 equiv.) and ACN (0.5 M). To the mixture was added DBU (2.0 equiv.)and the reaction was agitated at 120° C. in microwave for 25 min. LCMSof the crude mixture indicated formation of desired product as the majorspecies. The reaction mixture was concentrated in vacuo and the residuedirectly purified by flash chromatography (0-10% MeOH/DCM) to afford thedesired product ethyl9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylatein 49% isolated yield. LCMS (m/z) (M+H)=309.0, Rt=0.85 min.

Step 5:

Ethyl9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1.0 equiv.) was suspended in Water and Acetic Acid (4:1, 0.2 M) andconc. sulfuric acid (6.5 equiv.) was added to give a solution. Thereaction was heated at 110° C. for 3.5 hours. As the reactionprogressed, a solid precipitated out reaction. The reaction mixture wascooled to room temperature and the solid was collected by suctionfiltration and air-dried under vacuum overnight to afford the desiredproduct9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid in 80% isolated yield. LCMS (m/z) (M+H)=280.9, Rt=0.74 min.

Step 6:

9-chloro-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1.0 equiv.) was suspended in MeOH (0.08 M) and then NaBH₄ (3.46equiv.) was carefully added portion-wise. After complete NaBH₄ additionand when the effervescence had subsided, pTSOH.H₂O (0.1 equiv.) wasadded and the reaction was heated at 70° C. for 1 hour. The reaction wasquenched by the addition of acetone and concentrated under reducedpressure. The residue was diluted with EtOAc and sonicated to dissolvethe organics. Water was then added to dissolve the inorganic solids. Theorganic layer was separated and dried (MgSO₄), filtered and concentratedto give a yellow solid. The solid was dried under high vacuum for 30minutes to afford the desired product9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-onein 80% isolated yield. LCMS (m/z) (M+H)=239.3, Rt=0.85 min.

2-chloro-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-5-ol

Step 1:

5-ethoxy-3,6-dihydro-2H-1,4-oxazine (1.0 equiv.),2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 equiv.), triethylamine (0.2equiv.) were combined in Benzene (1.0 M) into a 40 mL vial. The mixturewas heated at 100° C. for 3 h and then LCMS indicated formation ofdesired product. M−H+=226.3, 0.71 min (basic method). The mixture wascooled to room temperature and the solvent evaporated in vacuo to affordquantitative yield of2,2-dimethyl-5-(morpholin-3-ylidene)-1,3-dioxane-4,6-dione. LCMS (m/z)(M−H)=226.3, Rt=0.71 min.

Step 2:

2,2-dimethyl-5-(morpholin-3-ylidene)-1,3-dioxane-4,6-dione (1.0 equiv.)and NaOMe (1.2 equiv.) were suspended in MeOH (0.3 M) in a vial and themixture heated to reflux. After 2 h, mostly desired product along withtrace unreacted starting material is observed. MH+=159.0, 0.29 (visibleby ELSD) is observed along with unreacted SM. The mixture was agitatedat reflux overnight. The next morning, the mixture was cooled to roomtemperature and then concentrated in vacuo. The residue was dissolved inSat'd NH₄Cl and extracted with EtOAc. The organic layer was dried(MgSO₄), filtered and concentrated in vacuo to afford (Z)-methyl2-(morpholin-3-ylidene)acetate in 95% crude yield. LCMS (m/z)(M+H)=159.0, Rt=0.29 min.

Step 3:

(Z)-methyl 2-(morpholin-3-ylidene)acetate (1.0 equiv.) was dissolved in4:1 dioxane/AcOH (0.5 M). The mixture was added NaBH₄ in portions andthe mixture agitated at room temperature for 20 min upon which completeconversion to the desired product was observed by LCMS (m/z) (M+H)=160.10.10 min. The mixture was concentrated in vacuo until constant mass andthen dissolved in THF (0.5 M) and then Sat'd NaHCO₃ (100 mL) was added.Then CBZCl (1.0 equiv.) was added and the mixture was agitated at roomtemperature. LCMS after 1 h indicated formation of desired product. Thereaction mixture was diluted with EtOAc and the layers separated. Theorganic layer was washed with brine and dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(0-100% EtOAc/heptane) to afford the desired product benzyl3-(2-methoxy-2-oxoethyl)morpholine-4-carboxylate in 51% isolated yieldas a colorless oil. LCMS (m/z) (M+H)=294.3, Rt=1.16 min.

Step 4:

Benzyl 3-(2-methoxy-2-oxoethyl)morpholine-4-carboxylate (1.0 equiv.) wasdissolved in THF:MeOH:Water (3:2:1) (0.2 M) and then LiOH.H₂O (182 mg,4.33 mmol was added. The mixture was agitated at 50° C. for 1 h and thenat room temperature for 1 h. The reaction mixture was concentrated invacuo and the residue acidified to pH=1 using 6 N HCl and the productwas extracted with EtOAc. The organic layer was washed with brine anddried (MgSO₄), filtered and concentrated in vacuo to afford the crudeacid 2-(4-((benzyloxy)carbonyl)morpholin-3-yl)acetic acid inquantitative yield. LCMS (m/z) (M−H)=277.9, Rt=1.07 min.

Step 5:

2-(4-((benzyloxy)carbonyl)morpholin-3-yl)acetic acid (1.0 equiv.) wascharged into a flask and then Boc-anhydride (2.0 equiv.) and t-BuOH (1.0M) were added. Then DMAP (0.2 equiv.) was added which led toinstantaneous exotherm. The mixture was maintained at 50° C. in an oilbath for 1 h and concentrated in vacuo. The residue was purified byflash chromatography (0-40% EtOAc/heptane) to afford the desired productbenzyl 3-(2-(tert-butoxy)-2-oxoethyl)morpholine-4-carboxylate as aviscous colorless oil. LCMS (m/z) (M+H-tBu)=280.2, Rt=1.42 min.

Step 6:

Benzyl 3-(2-(tert-butoxy)-2-oxoethyl)morpholine-4-carboxylate (1.0equiv.) was dissolved in MeOH: EtOAc (1:1), 0.5 M and then Pd—C (0.14equiv.) was added. The mixture was evacuated and purged with hydrogen(three times) and finally, the mixture was agitated under 1 atmosphereof hydrogen overnight. The next morning, LCMS indicated formation ofdesired product. The reaction mixture was filtered through celite andthe filtrate concentrated in vacuo to constant mass, thus affordingtert-butyl 2-(morpholin-3-yl)acetate in 91% isolated yield. LCMS (m/z)(M+H)=202.1, Rt=0.65 min.

Step 7:

Into a 3-dram vial were charged tert-butyl 2-(morpholin-3-yl)acetate(1.2 equiv.), methyl 4,6-dichloropyridazine-3-carboxylate (1.0 equiv.)and DMF (0.3 M). To the mixture at room temperature was added DIEA (3.0equiv). The mixture was agitated in heating block at 70° C. After 5 h,the mixture was concentrated in vacuo and the residue purified by flashchromatography (0-100% EtOAc/heptane) to afford the desired productmethyl4-(3-(2-(tert-butoxy)-2-oxoethyl)morpholino)-6-chloropyridazine-3-carboxylatein 77% isolated yield. LCMS (m/z) (M+H)=372.1, Rt=1.25 min.

Step 8:

Methyl4-(3-(2-(tert-butoxy)-2-oxoethyl)morpholino)-6-chloropyridazine-3-carboxylate(1.0 equiv.) was dissolved in toluene (0.1 M) and then treated drop-wisewith 1.0 M KOtBu (1.1 equiv.) at room temperature. The mixture wasagitated for 30 min and then quenched by addition of Sat'd NH₄Cl. Theproduct was extracted with EtOAc. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo to afford 90% yield of the crudeproduct tert-butyl2-chloro-5-oxo-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazine-6-carboxylate;which was taken to the next step as such without any furtherpurification. LCMS (m/z) (M+H)=340.0, Rt=1.25 min.

Step 9:

Tert-butyl2-chloro-5-oxo-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazine-6-carboxylate(1.0 equiv.) was dissolved in TFA (0.14) and the mixture placed underreflux (bath temperature=90° C.). After 90 min at reflux, the entirereaction mixture was poured onto solid Na₂CO₃ and after theeffervescence had subsided, water (3 ml) was added and the productextracted twice with DCM. The organic layer was dried (MgSO₄), filteredand concentrated in vacuo to afford2-chloro-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-5(6H)-onein 30.9% isolated yield as a pale yellow solid. LCMS (m/z) (M+H)=240.3,Rt=0.61 min.

Step 10:

2-chloro-6a,7,9,10-tetrahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-5(6H)-one(1.0 equiv.) was suspended in MeOH (0.04 M) and then at room temperaturewas added NaBH₄ (2.0 equiv.). The mixture was agitated at roomtemperature for 10 min after which acetone was added to quench thereaction mixture. The volatiles were evaporated in vacuo and the residuetaken up in EtOAc and washed with sat'd NH₄Cl. The organic layer wasseparated and dried (MgSO₄), filtered and concentrated in vacuo toafford(trans)-2-chloro-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-5-olin quantitative yield. LCMS (m/z) (M+H)=242.3, Rt=0.45 min.

diethyl9-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5,5(6H)-dicarboxylate

Step 1:

To a solution of 4-bromo-2-fluorobenzaldehyde (1.0 equiv.) and K₂CO₃(1.15 equiv.) in DMF (1.0M) was added the morpholine (1.15 equiv.). Theresulting reaction mixture was heated under reflux for 2 h upon whichcomplete conversion to the desired product was observed. The reactionmixture was cooled to room temperature and let to stand overnight. Thenext morning, the reaction mixture was diluted with EtOAc and water andvigorously agitated. The organic layer was separated and washed withwater and then brine and dried (MgSO₄), filtered and concentrated invacuo and the residue was purified by flash chromatography (0-50%EtOAc/heptane) to afford the desired product4-bromo-2-morpholinobenzaldehyde in 90% isolated yield as a light yellowsolid. LCMS (m/z) (M+H)=271.8, Rt=1.33 min.

Step 2:

A mixture of 4-bromo-2-morpholinobenzaldehyde (1.0 equiv.), diethylmalonate (1.05 equiv.), piperidine (0.17 equiv.) and benzoic acid (0.11equiv.) in Toluene (1.0 M) was refluxed using a Dean-Stark trapovernight. The next morning, LCMS indicated formation of desiredproduct. The reaction mixture was concentrated in vacuo and the residuewas purified by flash chromatography (0-100% EtOAc/heptane) to afforddiethyl 2-(4-bromo-2-morpholinobenzylidene)malonate in 87% isolatedyield the desired product as a yellow syrup. LCMS (m/z) (M+H)=414.3,Rt=1.65 min.

Step 3:

Into a 250 mL RB flask was added diethyl2-(4-bromo-2-morpholinobenzylidene)malonate (1.0 equiv.) and thenAcetonitrile (0.1 M). Then, gadolinium(III) trifluoromethanesulfonate(0.1 equiv.) was added in one portion. The entire mixture was agitatedat 70° C. overnight. The crude reaction was cooled to room temperatureand then filtered through celite and the filtrate concentrated in vacuo.The residue diethyl9-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5,5(6H)-dicarboxylatewas put under high vacuum until constant mass. LCMS (m/z) (M+H)=413.9,Rt=2.80 min (product analysis method in SQ4); ¹H NMR (400 MHz, CDCl₃) δppm 6.83-6.92 (m, 3H) 4.10-4.29 (m, 4H) 3.84-4.04 (m, 3H) 3.60-3.74 (m,3H) 3.06-3.28 (m, 3H) 1.26 (t, J=7.15 Hz, 3H) 1.19 (t, J=7.09 Hz, 3H).

(9-bromo-1,2,4,4a,5,6-hexahydro[1,4]oxazino[4,3-a]quinoline-5,5-diyl)dimethanol

Step 1:

Diethyl9-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5,5(6H)-dicarboxylate(1.0 equiv.) was dissolved in DCM (0.3 M) and cooled to −78° C. ThenDIBAH (10.0 equiv.) (1.0 M in DCM) was added dropwise and the mixturelet to warm to room temperature and agitate overnight. The next morning,the reaction mixture was poured onto ice-cold 1N HCl and the productextracted with EtOAc. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(0-100% EtOAc/heptane) to afford the desired product(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5,5-diyl)dimethanolas a colorless solid in 77% isolated yield. LCMS (m/z) (M+H)=328.0,Rt=1.13 min.

(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol

Step 1:

Into a 250 mL RB flask was charged crude diethyl9-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5,5(6H)-dicarboxylate(1.0 equiv.) and the gummy residue was dissolved in DMSO (0.5 M). Thenwater (2.0 equiv.) followed by LiCl (2.0 equiv.) was added. The entiremixture was placed in an oil bath pre-heated to 180° C. After 1 h,complete decarboxylation was observed and the product mixture (3.5:1)was observed. RM cooled to room temperature and water (80 mL) was added.The mixture was extracted with EtOAc and the organic layer was dried(MgSO₄), filtered and concentrated in vacuo and the residue purified byflash chromatography (0-100% EtOAc/heptane) to afford the desiredproduct ethyl9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylateas a 3.5:1 diastereomeric mixture in 89% isolated yield. LCMS: (m/z)(M+H)=341.9, Rt=1.23 (minor) and Rt=1.30 (major) min. ¹H NMR (400 MHz,DMSO-d6) δ ppm 6.81-7.00 (m, 3H) 4.16-4.26 (m, 2H) 3.86-4.07 (m, 2H)3.48-3.75 (m, 2H) 3.30-3.40 (m, 2H) 2.78-3.09 (m, 3H) 2.56-2.71 (m, 1H)1.26-1.36 (m, 3H).

Step 2:

Into a 250 mL RB flask was added ethyl9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) and THF (0.3) and the mixture cooled to 0° C. Then Superhydride (3.0 equiv.) was added. The mixture was let to warm to roomtemperature over 2 h upon which complete reduction of the ester materialwas observed. The reaction mixture was quenched by drop-wise addition ofwater and the product extracted with EtOAc and the organic layer waswashed with Sat'd Na₂CO₃ and then dried (MgSO₄), filtered andconcentrated in vacuo. The residue was azeotroped with MeOH to affordthe desired product(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanolas a white solid in quantitative yield. LCMS: LCMS: (m/z) (M+H)=299.9,Rt=1.26 min.

9-bromo-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide

Step 1:

Ethyl9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was dissolved in THF:MeOH:Water (3:2:1) (0.25 M) and thenLiOH.H₂O 5.0 equiv.) was added. The mixture was agitated at 50° C. for 1h during which complete hydrolysis of the ester was observed. Thereaction mixture was concentrated in vacuo. The residue was acidified topH=1 using 4N aq. HCl and the product was back extracted with EtOAc. Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo toafford quantitative yield of desired product. The residue9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid was taken to the next step without any further purification. LCMS:(m/z) (M+H)=313.9, Rt=1.24 min (minor) and Rt=1.29 (major).

Step 2:

Into a vial were charged9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (1.0 equiv.), EDC.HCl (1.2 equiv.), HOAT (1.2 equiv.), and DMF (0.3M). To the mixture was added DIEA (2.5 equiv.) followed by Methylamine(2.0 M in THF) (1.2 equiv.) and the mixture agitated at room temperatureovernight. The next morning, the reaction mixture was diluted with EtOAcand washed with water and then with sat'd Na₂CO₃ and dried (MgSO₄),filtered and concentrated in vacuo and the residue9-bromo-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamidewas obtained in quantitative yield and was taken to the next step assuch. LCMS: (m/z) (M+H)=326.9, Rt=1.18 min.

(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol

Step 1:

Ethyl9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was dissolved in THF (0.2 M) and cooled to −78° C. Then LDA(1.3 equiv.) was added. Then the mixture was agitated for 30 min andthen NFSI was added neat and the mixture let to warm to room temperatureand agitate over 72 h. The reaction mixture was quenched by addition ofwater and Sat'd NH₄Cl and the product extracted with EtOAc. The combinedorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by flash chromatography (0-50% EtOAc/heptane) toafford the desired product ethyl9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylatein 84% isolated yield. LCMS: (m/z) (M+H)=360.2, Rt=1.51 min.

Step 2:

ethyl9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was dissolved in THF (0.1 M) and cooled in ice-bath. To themixture was added Super-hydride (5.0 equiv.) and the mixture let to warmto room temperature overnight. The next morning, the reaction mixturewas quenched by addition of water and then diluted with EtOAc and washedwith Sat'd Na₂CO₃. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo and the residue azeotroped twice with MeOH anddried under high vacuum to afford the desired product(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanolin a 5:1 diastereomeric ratio. LCMS: (m/z) (M+H)=318.2, Rt=1.83 (minor)and Rt=1.85 min (major).

9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carbonitrile

Step 1:

Ethyl9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was dissolved in THF (0.15 M) and cooled to −78° C. ThenLDA (1.30 equiv.) was added. Then the mixture was agitated for 60 minand then 2.0 M MBTE solution of iodomethane (2.0 equiv.) was added. Themixture was warmed to room temperature and agitated for 1 h and thenquenched by addition of water and then sat'd NH₄Cl. The product wasextracted with EtOAc and the organic layer was dried (MgSO₄), filteredand concentrated in vacuo to afford the crude product ethyl9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylatein a 2.6:1 diastereomeric ratio, which was taken to the next stepwithout any further purification. LCMS: (m/z) (M+H)=356.2, Rt=1.30(major) and Rt=1.34 (minor) min.

Step 2:

9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was dissolved in THF:MeOH:water (3:2:1 ratio) (0.1 M) andthen LiOH.H₂O (5.0 equiv.) was added. The mixture was agitated at 70° C.in a heating block for 1 h. The mixture was then concentrated in vacuo.The residue was acidified with 6N HCl and the product extracted withEtOAc. The organic layer was dried (MgSO₄), filtered and concentrated invacuo to afford the desired product9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid, which was taken to the next step as such without any furtherpurification. LCMS: (m/z) (M+H)=328.1, Rt=1.01 (major) and 1.04 (minor)min (SQ4).

Step 3:

9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (1.0 equiv.), NH₄Cl (4.0 equiv.), HATU (1.3 equiv.) were combinedin DMF (0.2 M). To the mixture was then DIEA (50 equiv.) was added. Themixture was agitated at room temperature for 1 h upon which completeconversion to the desired diastereomeric products was observed. Thereaction mixture was dissolved in EtOAc and washed with Na₂CO₃ (sat'd)and then with water and then with brine. The organic layer was dried(MgSO₄), filtered and concentrated in vacuo. The residue9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamidewas taken to the next step as such without any further purification.LCMS: (m/z) (M+H)=327.2, Rt=0.89 (major) and Rt=0.90 (minor) min (SQ4).

Step 4:

9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide(1.0 equiv.) was dissolved in DCM (0.2 M) and then Triethylamine (6.0equiv.) was added. Then TFAA (4.5 equiv.) was added and the mixtureagitated at room temperature for 2 h and the concentrated in vacuo. Theresidue was taken up in EtOAc and washed with Sat'd NH₄Cl and then withNa₂CO₃ and then brine and dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by flash chromatography (0-30%EtOAc/heptane) to afford the desired products. Diastereomer 1 (Syn)9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carbonitrile:LCMS: (m/z) (M+H)=309.3, Rt=0.56 min, Diastereomer 2 (non-polar): LCMS:(m/z) (M+H)=309.3, 0.71 min.

tert-butyl(9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)carbamate

Step 1:

Into a RB flask was charged9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (1.0 equiv.), tert-butanol 50 equiv.), DIEA (2.5 equiv.) and thenDPPA (1.25 equiv.). The mixture was refluxed at 110° C. overnight. Thenext morning, the reaction mixture was concentrated in vacuo and theresidue purified by flash chromatography (0-30% EtOAc/heptane) to affordthe desired product tert-butyl(9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)carbamatein 13.9% isolated yield. LCMS: (m/z) (M+H)=399.3, Rt=1.18 min.

10-bromo-1,2,4,4a,5,6-hexahydro-8H-pyrido[2′,1′:2,3]pyrimido[6,1-c][1,4]oxazin-8-one

Step 1:

tert-butyl 2-(morpholin-3-yl)acetate (1.0 equiv.),4-bromo-2,6-difluoropyridine (1.0 equiv.) and DIEA (3.0 equiv.) werecombined in EtOH (0.5 M) were placed in a screw-capped vial and themixture was heated at 100° C. for 48 h and cooled to room temperatureand then concentrated in vacuo. The residue was purified by flashchromatography (0-50% EtOAc/heptane) to afford the desired producttert-butyl 2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)acetate asa colorless oil in 33% isolated yield. LCMS: (m/z) (M+H-56)=320.9,Rt=1.69 min.

Step 2:

Tert-butyl 2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)acetate(1.0 equiv.) was dissolved in DCM (0.2 M) and at room temperature wasadded TFA (58.4 equiv.). The mixture was agitated for 2 h and thenconcentrated in vacuo. The residue was dissolved in EtOAc and washedwith water and dried (MgSO₄), filtered and concentrated in vacuo. Theresidue 2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)acetic acidwas taken to the next step as such. LCMS: (m/z) (M+H-56)=319.1, Rt=1.23min.

Step 3:

2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)acetic acid (1.0equiv.) was dissolved in Tetrahydrofuran:Dioxane (1:1, 0.3 M) and thencooled to −15° C. Then 4-methylmorpholine (1.0 equiv.) followed byisobutyl chloroformate (1.0 equiv.) were added. The mixture was agitatedfor 10 min after which NaBH₄ (2.0 equiv.) dissolved in water (1 mL/20 mgof NaBH₄) was added. The mixture was let to warm to room temperatureover 10 min and the mixture was quenched with acetone and the volatileswere evaporated in vacuo. The residue was taken up in EtOAc and washedtwice with 1.0 N NaOH (to remove unreacted acid starting material). Theorganic layer was washed with brine and dried (MgSO₄), filtered andconcentrated in vacuo. The residue2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)ethanol obtained in65.6% yield was taken to the next step without any further purification.LCMS: (m/z) (M+H)=306.9, Rt=1.24 min.

Step 4:

2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)ethanol (1.0 equiv.)was dissolved in DCM (0.1M) and Et₃N (5.0 equiv.) was added. The mixturewas cooled to 0° C. and then MsCl (1.1 equiv.) was added dropwise. Themixture was agitated for 30 min in ice bath and then the solvent wasremoved in vacuo to afford2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)ethyl methanesulfonatein quantitative crude yield. LCMS: (m/z) (M+H)=384.9, Rt=1.38 min.

Step 5:

2-(4-(4-bromo-6-fluoropyridin-2-yl)morpholin-3-yl)ethyl methanesulfonate(1.0 equiv.) was dissolved in dry-THF (0.05 M) and heated to reflux for2 h. At this stage, Sat'd NaHCO₃ (5 mL) was added and the mixture heatedat 60° C. for 2 h. The mixture was cooled to room temperature andextracted with EtOAc. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(0-10% MeOH/DCM) to afford the desired product10-bromo-4,4a,5,6-tetrahydro-1H-pyrido[2′,1′:2,3]pyrimido[6,1-c][1,4]oxazin-8(2H)-onein 42% isolated yield. LCMS: (m/z) (M+H)=38286.9, Rt=0.95 min.

10-(5-amino-2-methylpyridin-3-yl)-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol

Step 1: A mixture of 5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine (0.75equiv.) and ethyl 3-(4-bromo-2-fluorophenyl)-3-oxopropanoate (1 equiv.)was heated in a sealed tube at 70° C. for 72 hr. The reaction mixturewas allowed to come to r.t., diluted with minimum amount of DCM. It waspurified by flash chromatography over silica gel (DCM with 10% MeOH) togive ethyl10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylatein 64.5% yield. LCMS (m/z) (M+H)=367.9, Rt=1.12 min.

Step 2:

To a solution of ethyl10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylate(1 equiv.) in THF:MeOH (3:2 ratio) was added solution of LiOH.H₂O (5equiv.) in water (ratio 2, final concentration of reaction mixture;0.19M). The reaction mixture was heated at 65° C. for 30 min. Thereaction mixture was concentrated under reduced pressure and acidifiedto pH˜1 by using 4N HCl in water. The solid obtained was filtered andthe precipitate was air dried under vacuum to give10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylicacid in 87% yield. LCMS (m/z) (M+H)=339.8, Rt=1.13 min.

Step 3:

To a cooled mixture of10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylicacid (1 equiv.) at 0° C. in THF (0.15M), was dropwise added L-selectride(10 equiv.), and the reaction mixture was allowed to come to ambienttemperature. It was further stirred at ambient temperature for another 2hr. The reaction mixture was quenched with dropwise addition of MeOHuntil the effervescence has subsided. Then additional MeOH was addedfollowed by p-toluenesulfonic acid monohydrate (0.1 eq.) and heated at70° C. for 1.5 hr. The cooled reaction mixture was concentrated underreduced pressure, diluted with EtOAc, washed with water. The organicextracts were dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified by flash chromatography over silica gel(heptanes with 60% ethyl acetate) to give10-bromo-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-onein 39% yield. LCMS (m/z) (M+H)=297.9, Rt=1.26 min.

Step 4:

To a cooled mixture of10-bromo-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-one(1 equiv.) at −20° C. in THF (0.1M), was d added L-selectride (4equiv.), and the reaction mixture was allowed to come to ambienttemperature over 1 hr. The reaction mixture was quenched with dropwiseaddition of H₂O. The reaction mixture was concentrated under reducedpressure, diluted with EtOAc, washed with sat. NH₄Cl solution. Theorganic extracts were dried over magnesium sulfate, filtered, andconcentrated The crude product was purified by flash chromatography oversilica gel (heptanes with 100% ethyl acetate) to give10-bromo-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol in100% yield. LCMS (m/z) (MH−H₂O)⁺=281.9, Rt=1.20 min.

Step 5:

A mixture of10-bromo-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol (1equiv6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(1.2 equiv.), Xphos G2-Pd-Cy (0.1 equiv.) and K₃PO₄ (2 equiv.) indioxane:H₂O (0.08 M, 6:1 ratio) was irradiated in a microwave vial for30 min at 130° C. The cooled crude product was purified by flashchromatography over silica gel (DCM with 15% MeOH) to give the desiredproduct10-(5-amino-2-methylpyridin-3-yl)-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol(56%). LCMS (m/z) (MH−H₂O)⁺=326.1, Rt=0.72 min.

Synthesis of(rac)-(4a,10b-cis)-9-bromo-6-ethyl-4,4a,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneand(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

Step 1:

To a stirred solution of tetrahydropyran-4-one (1.0 equiv) in toluene(0.5 M) at −78° C. was slowly added LiHMDS (1 M in THF, 1.1 equiv) andthe mixture was stirred for 30 min. Ethyl chloroformate (1.15 equiv) wasthen added and the reaction was allowed to warm to RT over 15 min. Thereaction was quenched by the addition of saturated aqueous NH₄Cl. Thelayers were separated; the organics were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was adsorbed on Celiteand purified by flash chromatography over silica gel (heptane with 0-40%ethyl acetate gradient) to give ethyl4-oxotetrahydro-2H-pyran-3-carboxylate, as a colorless oil in 18% yield.LCMS (m/z) (M+H)=344.0, Rt=1.13 min. ¹H NMR (400 MHz, Chloroform-d) δ11.71 (s, 1H), 4.11 (t, J=1.7 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.69 (t,J=5.7 Hz, 2H), 2.23 (tt, J=5.7, 1.7 Hz, 2H), 1.13 (t, J=7.1 Hz, 3H).

Step 2:

To a stirred solution of ethyl 4-oxotetrahydro-2H-pyran-3-carboxylate(1.0 equiv) in THF (0.4 M) at 25° C. was slowly added 60% NaH (1.3equiv) and the mixture was stirred for 2 h and then cooled to −78° C.N-phenyl-bis(trifluoromethanesulfonamide) (1.1 equiv) was then added andthe reaction was allowed to warm to RT and stirred overnight. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted twicewith EtOAc. The combined organics were dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography oversilica gel (heptanes with 0-30% ethyl acetate gradient) to give ethyl4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate,as a light yellow oil in 122% yield. The excess yield is due tocontamination from phenyltriflamide byproducts. 1H NMR (400 MHz,Chloroform-d) δ 4.45 (t, J=2.8 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 3.89 (t,J=5.5 Hz, 2H), 2.53 (tt, J=5.5, 2.7 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).

Step 3:

A stirred solution of4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate(1.0 equiv), 5-bromo-2-fluoropyridine-3-boronic acid (1.05 equiv), andK2CO3 (2.5 equiv) in THF (0.2 M) was purged with N₂ for 5 min. Pd(Ph₃P)₄(0.05 equiv) was added, and the mixture was purged again for 5 min andthen heated at 65° C. for 4 h. The reaction was poured onto water andextracted twice with EtOAc The combined organics were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was adsorbedon Celite and purified by flash column chromatography over silica gel(heptane with 0-30% ethyl acetate gradient) to give ethyl4-(5-bromo-2-fluoropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate as acolorless oil in 66% yield. LCMS (m/z) (M+H)=330.0/332.0, Rt=1.04 min.¹H NMR (400 MHz, Chloroform-d) δ 8.20 (dd, J=2.4, 1.4 Hz, 1H), 7.66 (dd,J=8.2, 2.5 Hz, 1H), 4.47 (t, J=2.8 Hz, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.90(t, J=5.5 Hz, 2H), 2.46 (tt, J=5.5, 2.8 Hz, 2H), 1.04 (t, J=7.1 Hz, 3H).

Step 4:

To a solution of ethyl4-(5-bromo-2-fluoropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate (1.0equiv) in THF/MeOH (1:1; 0.05 M) at −78° C. under Ar was added SmI2 (0.1M in THF, 5 equiv) dropwise. After addition, the solution was stirredunder Ar at −78° C. for 2 hr. The reaction was quenched withhalf-saturated NaHCO₃, warmed to RT, and concentrated to remove excessTHF/MeOH. The remaining mixture was extracted three times with EtOAc,and the combined organics were washed with brine, dried over MgSO₄,filtered, and concentrated. The crude material was adsorbed on Celiteand purified by flash chromatography over silica gel (heptane with 0-30%ethyl acetate gradient) to give 4 ethyl4-(5-bromo-2-fluoropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate as adiastereomeric mixture as a colorless oil in 58% yield. LCMS (m/z)(M+H)=332.1/334.1, Rt=0.99 and 1.03 min.

Step 5:

To a solution of 4 ethyl4-(5-bromo-2-fluoropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate (1.0equiv) in DMSO (0.2 M) were added i-Pr₂NEt (5 equiv) and EtNH₂ (2 M inTHF, 3 equiv) and the mixture was heated at 120° C. for 72 h. Thereaction was cooled to RT, poured onto half-saturated NH₄Cl, andextracted twice with EtOAc The combined organics were washed with waterbrine, dried over MgSO₄, filtered, and concentrated. The crude materialwas adsorbed on Celite and purified by flash chromatography over silicagel (heptane with 0-30% ethyl acetate gradient) to give(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas the earlier-eluting isomer as a white solid in 39% yield. LCMS (m/z)(M+H)=311.0/313.0, Rt=1.03 min. ¹H NMR (400 MHz, Chloroform-d) δ 8.32(dd, J=2.3, 1.0 Hz, 1H), 7.53 (dd, J=2.2, 1.4 Hz, 1H), 4.51 (dd, J=11.9,4.6 Hz, 1H), 4.20 (dt, J=13.8, 6.9 Hz, 2H), 4.12-4.00 (m, 1H), 3.57-3.48(m, 2H), 2.86-2.75 (m, 1H), 2.38 (ddd, J=14.7, 10.5, 4.6 Hz, 1H), 2.17(ddd, J=11.2, 4.0, 2.0 Hz, 1H), 1.74 (qd, J=12.5, 4.6 Hz, 1H), 1.20 (t,J=7.0 Hz, 4H). The later-eluting isomer was isolated to giv(rac)-(4a,10b-cis)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white solid in 42% yield. LCMS (m/z) (M+H)=311.0/313.0, Rt=0.97min. 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.3 Hz, 1H), 7.56 (d,J=2.4 Hz, 1H), 4.77-4.68 (m, 1H), 4.33-4.21 (m, 1H), 4.19-4.09 (m, 1H),4.00 (ddd, J=11.5, 4.1, 2.3 Hz, 1H), 3.58-3.46 (m, 2H), 3.09 (dt,J=11.8, 5.1 Hz, 1H), 2.68-2.60 (m, 1H), 1.80-1.66 (m, 1H), 1.61 (d,J=2.8 Hz, 1H), 1.22 (t, J=7.0 Hz, 4H).

Synthesis of(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4a-methyl-1,2,4,4a,6,10b-hexahydro-5H-pyrano[3,4-c][1,8]naphthyridin-5-one

To a stirred solution of9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(mixture of diastereomers, 1 equiv) in THF (0.05 M) at −78° C. was addedLDA (2 M in THF/heptane/ethyl benzene, 2 equiv) and the mixture wasstirred for 30 min. MeI (equiv) was then added, and the mixture wasstirred for 2 h. The reaction was quenched with saturated aqueous NH₄Cland extracted twice with EtOAc The combined organics were washed withbrine, dried over MgSO₄, filtered, and concentrated. The so-obtainedresidue was used as9-bromo-6-ethyl-4a-methyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onewithout further purification. LCMS (m/z) (M+H)=325.1/327.1, R_(t)=1.05min.

Synthesis of2-chloro-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine

Step 1:

A vial was charged with 2,3,5-trichloropyridazine (1 equiv),morpholin-3-ylmethanol (1 equiv), DMF (1 M), and triethylamine (3equiv). The resulting solution was heated to 90° C. for 6 h. Thereaction mixture was cooled to room temperature, diluted with sat. aq.ammonium chloride solution and water, then extracted with EtOAc (4×).The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered, and concentrated. The residue was taken up in etherand stirred overnight. In the morning, the mixture was filtered, and thecollected solid was washed with ether (2×), then dried under a flow ofN₂ (g) to give (4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)methanol(52% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (s, 1H)4.53-4.91 (m, 1H) 4.04-4.24 (m, 1H) 3.73-3.92 (m, 3H) 3.44-3.70 (m, 4H)3.16 (br d, J=11.49 Hz, 1H). LCMS (m/z) (M+H)=264.2, Rt=0.79 min.

Step 2:

A round-bottom flask was charged with(4-(3,6-dichloropyridazin-4-yl)morpholin-3-yl)methanol (1 equiv) and DCM(0.2 M) to give a suspension. The flask was cooled in an ice-water bathfor 5 min, then Dess-Martin periodinane (1.2 equiv) was added in oneportion. After 1.5 h, the cooling bath was removed. The mixture wasstirred for 2 h, then an additional portion of Dess-Martin (1.2 equiv)was added. After another 20 min of stirring, the mixture was dilutedwith sat. aq. sodium bicarbonate, then extracted with DCM (2×). Thecombined organic extracts were washed with aq. sodium thiosulfatesolution (1×), which was back-extracted with DCM. The combined organicextracts were dried over sodium sulfate, filtered, and concentrated. Theresidue was concentrated from acetone (2×). The resulting solid wastaken up in acetone then filtered and dried to give a tan solid.Filtration was repeated with the filtrate, and the two solids werecombined. The solid was purified by chromatography on silica gel (24-gRedi-Sep column, 80-100% EtOAc/heptane) to give4-(3,6-dichloropyridazin-4-yl)morpholine-3-carbaldehyde (50% yield) as alight-yellow solid. NMR was consistent with about 80% desired aldehyde.LCMS (m/z) (M+H₂O+H)=280.2, Rt=0.75 min.

Step 3:

An ice-cold solution of4-(3,6-dichloropyridazin-4-yl)morpholine-3-carbaldehyde (1 equiv) in THF(0.1 M) was treated with a solution of ethylmagnesium bromide (1M inTHF, 2 equiv). The cooling bath was removed, and the mixture was stirredfor 1 h. The reaction mixture was diluted with sat. aq. ammoniumchloride solution and extracted with EtOAc (3×). The combined organicextracts were dried over sodium sulfate, filtered, and concentrated togive a light-yellow foam. The residue was dissolved in DMF (0.1 M).Sodium hydride (60 wt % in mineral oil, 1.5 equiv) was added, and theresulting mixture was heated to 70° C. for 6 h. The mixture was thencooled to room temperature, diluted with water, and extracted with EtOAc(3×). The combined organic extracts were dried over sodium sulfate,filtered, and concentrated. The residue was purified by chromatographyon silica gel (80-100% EtOAc/heptane) to give2-chloro-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine(63% yield) as a mixture of stereoisomers. LCMS (m/z) (M+H)=256.1,Rt=0.89 min.

Synthesis of trans- and cis-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate

A round-bottom flask was charged with diethyl9-chloro-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,5(6H)-dicarboxylate(1 equiv), LiCl (2 equiv), DMSO (0.5 M), and water (2 equiv). The flaskwas fitted with a reflux condenser and heated to 180° C. for 6 h, andthe mixture was cooled to room temperature overnight. In the morning,the mixture was diluted with water and a small amount of brine, thenextracted with EtOAc (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel (0-50% EtOAc/heptane). The first elutingspot was collected to give trans-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(69.0% yield); LCMS (m/z) (M+H) 297.0; Rt.=1.08 min. The second elutingspot was collected to give cis-ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(15.91% yield). LCMS (m/z) (M+H) 297.0; Rt.=0.93 min.

Intermediate 1. Synthesis of2-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)propan-2-ol

Step 1:

To an ice cold solution of ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1.0 equiv.) in THF (0.07 M) was added MeMgI (7 equiv.) and allowed tocome to ambient temperature. It was stirred for 2 hr and then placedback in the ice bath. The reaction mixture was quenched with NH₄Cl andextracted with DCM. The organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (heptanes with 100%ethyl acetate) to give2-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)propan-2-olin 78% yield of two peaks after chiral separation. LCMS (m/z)(M+H)=283.1, Rt=0.80 min.

Intermediate 2. Synthesis of2-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)propan-2-ol

Step 1:

To an ice cold solution of ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1.0 equiv.) in THF (0.07 M) was added MeMgI (7 equiv.) and allowed tocome to ambient temperature. It was stirred for 2 hr and then placedback in the ice bath. The reaction mixture was quenched with NH₄Cl andextracted with DCM. The organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (heptanes with 100%ethyl acetate) to give2-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)propan-2-olin 100% yield of two peaks after chiral separation. LCMS (m/z)(M+H)=283.2, Rt=0.75 min.

Synthesis of10-(5-amino-2-methylpyridin-3-yl)-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol

Step 1:

A mixture of 5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine (0.75 equiv.) andethyl 3-(4-bromo-2-fluorophenyl)-3-oxopropanoate (1 equiv.) was heatedin a sealed tube at 70° C. for 72 hr. The reaction mixture was allowedto come to r.t., diluted with minimum amount of DCM. It was purified byflash chromatography over silica gel (DCM with 10% MeOH) to give ethyl10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylatein 64.5% yield. LCMS (m/z) (M+H)=367.9, Rt=1.12 min.

Step 2:

To a solution of ethyl10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylate(1 equiv.) in THF:MeOH (3:2 ratio) was added solution of LiOH.H₂O (5equiv.) in water (ratio 2, final concentration of reaction mixture;0.19M). The reaction mixture was heated at 65° C. for 30 min. Thereaction mixture was concentrated under reduced pressure and acidifiedto pH˜1 by using 4N HCl in water. The solid obtained was filtered andthe precipitate was air dried under vacuum to give10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylicacid in 87% yield. LCMS (m/z) (M+H)=339.8, Rt=1.13 min.

Step 3:

To a cooled mixture of10-bromo-7-oxo-1,2,5,7-tetrahydro-4H-[1,4]oxazepino[4,5-a]quinoline-6-carboxylicacid (1 equiv.) at 0° C. in THF (0.15M), was dropwise added L-selectride(10 equiv.), and the reaction mixture was allowed to come to ambienttemperature. It was further stirred at ambient temperature for another 2hr. The reaction mixture was quenched with dropwise addition of MeOHuntil the effervescence has subsided. Then additional MeOH was addedfollowed by p-toluenesulfonic acid monohydrate (0.1 eq.) and heated at70° C. for 1.5 hr. The cooled reaction mixture was concentrated underreduced pressure, diluted with EtOAc, washed with water. The organicextracts were dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified by flash chromatography over silica gel(heptanes with 60% ethyl acetate) to give10-bromo-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-onein 39% yield. LCMS (m/z) (M+H)=297.9, Rt=1.26 min.

Step 4:

To a cooled mixture of10-bromo-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-one(1 equiv.) at −20° C. in THF (0.1M), was d added L-selectride (4equiv.), and the reaction mixture was allowed to come to ambienttemperature over 1 hr. The reaction mixture was quenched with dropwiseaddition of H₂O. The reaction mixture was concentrated under reducedpressure, diluted with EtOAc, washed with sat. NH₄Cl solution. Theorganic extracts were dried over magnesium sulfate, filtered, andconcentrated The crude product was purified by flash chromatography oversilica gel (heptanes with 100% ethyl acetate) to give10-bromo-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol in100% yield. LCMS (m/z) (MH−H₂O)⁺=281.9, Rt=1.20 min.

Step 5:

A mixture of10-bromo-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol (1equiv6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(1.2 equiv.), Xphos G2-Pd-Cy (0.1 equiv.) and K₃PO₄ (2 equiv.) indioxane:H₂O (0.08 M, 6:1 ratio) was irradiated in a microwave vial for30 min at 130° C. The cooled crude product was purified by flashchromatography over silica gel (DCM with 15% MeOH) to give the desiredproduct10-(5-amino-2-methylpyridin-3-yl)-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol(56%). LCMS (m/z) (MH−H₂O)⁺=326.1, Rt=0.72 min.

2-((9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-yl)oxy)ethan-1-ol

Step 1:

To an ice cold solution of9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(1.0 equiv.) in DMF (0.13 M) was added NaH (2.5 equiv.) and stirred for10 min. Then tert-butyl(2-iodoethoxy)dimethylsilane (2.5 equiv.) wasthen added and allowed the reaction mixture to come to ambienttemperature. It was stirred for 3 hr, quenched with water and extractedwith EtOAc. The organic phase was washed with sat. NaHCO₃. The combinedaqueous layer was back extracted with EtOAc. The combined organic phasewas washed with brine, dried over magnesium sulfate, filtered, andconcentrated. The crude product was purified by flash chromatographyover silica gel (hept with 0-100% ethyl acetate) to give9-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridinein 54.5% yield. LCMS (m/z) (M+H)=445.0, Rt=1.61 min.

Step 2:

To a solution of9-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(1 equiv.) in MeOH (0.2 M) was added 4M HCl in dioxane (20 equiv.) andstirred for 30 min. The reaction mixture was concentrated to dryness.The crude product was purified by flash chromatography over silica gel(DCM with 0-10% MeOH) to give2-((9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-yl)oxy)ethan-1-olin 43% yield. LCMS (m/z) (M+H)=331.0, Rt=0.76 min.

Step 1:

tert-butyl 5-(2-methoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate (2.096g, 7.67 mmol) was dissolved in THF (30 mL) and then LiOH.H₂O (1.609 g,38.3 mmol) dissolved in water (10 mL) was added. The mixture wasagitated at room temperature for 1 h and then concentrated in vacuo. Theresidue was acidified to pH=5 using 4N HCl (aq.), The product wasextracted with EtOAc and dried (MgSO₄), filtered and concentrated invacuo. The residue 2-(4-(tert-butoxycarbonyl)-1,4-oxazepan-5-yl)aceticacid was taken to the next step without any further purification. LCMS(m/z) (M+H-100)=160.1, Rt=0.98 min.

Step 2:

2-(4-(tert-butoxycarbonyl)-1,4-oxazepan-5-yl)acetic acid (1.989 g, 7.67mmol) was dissolved in Toluene (38.4 ml) and Et₃N (1.276 ml, 9.20 mmol)was added. To the mixture at room temperature was added DPPA (1.818 ml,8.44 mmol) and the mixture agitated for 10 min. Then, benzyl alcohol(1.196 ml, 11.51 mmol) was added and the mixture heated to 110° C.overnight. The next morning, the mixture was concentrated in vacuo andthe residue purified by flash chromatography (0-50% EtOAc/heptane, 80gram column, 30 min) to afford tert-butyl5-((((benzyloxy)carbonyl)amino)methyl)-1,4-oxazepane-4-carboxylate in55% isolated yield. LCMS (m/z) (M+Na)=387.1, Rt=1.38 min.

Step 3:

Tert-butyl5-((((benzyloxy)carbonyl)amino)methyl)-1,4-oxazepane-4-carboxylatecarboxylate (1.0 equiv.) in MeOH (0.1 M) was added 10% Pd—C (0.15equiv.). The reaction mixture was purged with hydrogen and hydrogenatedwith a balloon hydrogen overnight. The reaction mixture was filteredthrough a celite pad, and the pad was rinsed with MeOH. Filtrate wasconcentrated to dryness under reduced pressure to give product,tert-butyl 5-(aminomethyl)-1,4-oxazepane-4-carboxylate in 96% yield.LCMS (m/z) (M+H)=231.1, Rt=0.65 min.

Step 4:

Used the standard peptide coupling method used before. LCMS (m/z)(M+H)=334.1 (deboc fragment), Rt=1.26 min.

Step 5:

To an ice cold solution of tert-butyl5-((5-bromo-3-fluoropicolinamido)methyl)-1,4-oxazepane-4-carboxylate(1.0 equiv.) in DMF (0.19 M) was added NaH (2.5 equiv.) and stirred for1 hr. Bromoethane (2.5 equiv.) was then added and allowed the reactionmixture to come to ambient temperature. It was stirred for 1 hr,quenched with water and extracted with EtOAc. The organic phase waswashed with sat. NaHCO₃. The combined aqueous layer was back extractedwith EtOAc. The combined organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (hept with 0-100% ethylacetate) to give tert-butyl5-((5-bromo-N-ethyl-3-fluoropicolinamido)methyl)-1,4-oxazepane-4-carboxylatein 74% yield. LCMS (m/z) (M+H)=362.1, Rt=1.36 min.

Step 6:

To a solution of tert-butyl5-((5-bromo-N-ethyl-3-fluoropicolinamido)methyl)-1,4-oxazepane-4-carboxylate(1 equiv.) in DCM (0.21 M) was added 4M HCl in dioxane (5 equiv.) andstirred for 1 hr. The reaction mixture was concentrated to dryness togive the desired product,N-((1,4-oxazepan-5-yl)methyl)-5-bromo-N-ethyl-3-fluoropicolinamide in100% yield. LCMS (m/z) (M+H)=36.0, Rt=0.75 min.

Step 7:

to a solution ofN-((1,4-oxazepan-5-yl)methyl)-5-bromo-N-ethyl-3-fluoropicolinamide (1equiv.) in NMP (0.21 M) was added DIPEA (6 equiv.) and the reactionmixture was stirred at 70° C. for 18 hrs. The reaction mixture wasdiluted with EtOAc, washed with water, brine, dried over sodium sulfate,filtered, and concentrated. The crude product was purified by C18 flashISCO reverse phase column (no modifier) to give11-bromo-7-ethyl-1,2,5,5a,6,7-hexahydropyrido[2′,3′:6,7][1,4]diazepino[1,2-d][1,4]oxazepin-8(4H)-onein 38.4% yield. Two peaks were isolated after chiral separation. LCMS(m/z) (M+H)=342.0, Rt=0.93 min.

Synthesis of9-bromo-6-ethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one

Step 1:

To a stirred solution of 2-chloro-5-bromo-3-nitropyridine (1.0 equiv) inDMSO (0.9 M) at 25° C. were added ethylamine (2 M in THF, 1.1 equiv) andEt₃N (1.8 equiv) and the reaction was stirred overnight. The reactionwas poured onto water, stirred for 10 min, and then filtered. Theso-obtained yellow solid was dried to provide5-bromo-N-ethyl-3-nitropyridin-2-amine in 96% yield which was usedwithout further purification. LCMS (m/z) (M+H)=246.0/248.0, Rt=1.13 min.

Step 2:

To a stirred solution of 5-bromo-N-ethyl-3-nitropyridin-2-amine (1.0equiv) in 2.5:1 EtOH/water (0.36 M) at 25° C. were added NH₄Cl (5 equiv)followed by portionwise addition of Fe (5 equiv) and the reaction washeated to 105° C. and stirred for 4 h. The reaction was cooled to RT,diluted with EtOAc, and filtered through Celite. The filtrated wasconcentrated and purified by flash column chromatography over silica gel(heptane and 0-100% EtOAc gradient) to give5-bromo-N2-ethylpyridine-2,3-diamine as a purple solid in 57% yield.LCMS (m/z) (M+H)=216.0/218.0, Rt=0.42 min.

Step 3:

Solutions of 5-bromo-N2-ethylpyridine-2,3-diamine (1.0 equiv) in THF(0.2 M) and malonyl chloride (1.2 equiv) in THF (0.25 M) weresimultaneously added dropwise over 1 h (via syringe pumps) to a flaskcharged with THF (0.1 M relative to starting material) at 0° C. Afteraddition was complete, the reaction was allowed to warm to 25° C. andstirred for 4.5 h. The reaction was concentrated. The residue waspurified by flash column chromatography over silica gel (heptane and0-100% EtOAc gradient) to provide8-bromo-5-ethyl-1H-pyrido[2,3-b][1,4]diazepine-2,4(3H,5H)-dione as awhite solid in 42% yield. LCMS (m/z) (M+H)=283.9/285.9, Rt=0.71 min.

Step 4:

To a solution of8-bromo-5-ethyl-1H-pyrido[2,3-b][1,4]diazepine-2,4(3H,5H)-dione (1.0equiv) in THF (0.14 M) at 0° C. were added dimethylamine (2 M in THF,2.0 equiv) followed by TiCl₄ (1 M in DCM, 1.6 equiv) and the mixture wasallowed to warm to RT and stirred for 3 h. The reaction mixture wasdiluted with EtOAc and brine and filtered through Celite. The filtratewas washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash column chromatography over silica gel(heptane and 0-100% EtOAc gradient) to provide8-bromo-2-(dimethylamino)-5-ethyl-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-oneas a pale yellow oil in 78% yield. LCMS (m/z) (M+H)=311.0/313.0, Rt=1.00min.

Step 5:

A mixture of8-bromo-2-(dimethylamino)-5-ethyl-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-one(1.0 equiv) and formic acid hydrazide (2.0 equiv) in 10:1 DowthermA/acetic acid (0.2 M) was heated to 150° C. and stirred for 2 h. Thereaction mixture was diluted with DCM and purified by flash columnchromatography over silica gel (DCM and 0-15% MeOH gradient) to give9-bromo-6-ethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-oneas a white solid in 75% yield. LCMS (m/z) (M+H)=308.0/310.0, Rt=0.67min.

Synthesis of9-bromo-6-ethyl-4,4-dimethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one,Methyl2-(4-(5-bromo-2-(ethyl(methyl)amino)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropanoate

9-bromo-6-ethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one(1.0 equiv) was dissolved in DMF (0.1 M); the solution was cooled to 0°C. and sodium hydride (2.0 equiv) was slowly added. The reaction wasstirred at 0° C. for 30 minutes, and then iodomethane (2.5 equiv) wasadded and the reaction was stirred at room temperature for 45 minutes.The reaction mixture was poured onto saturated aqueous NH₄Cl andextracted three times with EtOAc. The combined organics were washed withwater and brine, dried over MgSO₄, filtered and concentrated. Theso-obtained residue was used as9-bromo-6-ethyl-4,4-dimethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-onewithout further purification. LCMS (m/z) (M+H)=336.0/338.0, Rt=0.85 min.

Synthesis of9-bromo-5-ethyl-4H-pyrido[2,3-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6(5H)-one

Step 1:

To a stirred solution of ethylamine (2 M in THF, 4.0 equiv) in MeCN (2.0M) at 0° C. was added ethyl bromoacetate (1.0 equiv) and the mixture wasallowed to warm to RT and stirred for 2 h. The reaction mixture wasconcentrated and then partitioned between EtOAc and 1 M NaOH. Theaqueous layer was extracted with more EtOAc, and the combined organicswere dried over MgSO₄, filtered, and concentrated. The so-obtainedresidue was used as ethyl 2-(ethylamino)acetate (59% yield) withoutfurther purification. ¹H NMR (400 MHz, Chloroform-d) δ 4.19 (q, J=7.2Hz, 2H), 3.40 (s, 2H), 2.65 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H),1.12 (t, J=7.1 Hz, 3H).

Step 2:

A stirred mixture of 5-bromo-3-nitropicoline (1.0 equiv) and KMnO₄ (2.0equiv) in water (0.2 M) was heated to 80° C. and stirred for 2 h. MoreKMnO₄ (4 equiv) was added, and the reaction was further heated to 100°C. and stirred overnight. The mixture was cooled and filtered throughCelite while still slightly warm, washing with H₂O and EtOAc. Thefiltrate was extracted twice with EtOAc, and those organic extracts werediscarded. The aqueous layer was acidified with HCl and extracted twicemore with EtOAc. These combined organics were washed with brine, driedover MgSO₄, filtered and concentrated to 5-bromo-3-nitropicolinic acidas a yellow solid in 2.4% yield which was used without fatherpurification. LCMS Rt=0.39 min.

Step 3:

5-bromo-3-nitropicolinic acid (1.0 equiv) and ethyl2-(ethylamino)acetate (1.1 equiv) were taken up in DMA (0.15 M) at 25°C. HOAT (1.3 equiv), iPr₂EtN (3 equiv), and EDC (1.3 equiv) were addedand the mixture was stirred overnight at 25° C. The mixture was pouredonto water and extracted three times with ethyl acetate. The combinedorganics were washed with water and brine, dried over magnesium sulfate,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togive ethyl 2-(5-bromo-N-ethyl-3-nitropicolinamido)acetate as a colorlessoil in 69% yield. LCMS (m/z) (M+H)=360.1/362.1, Rt=0.92 min.

Step 4:

To a stirred solution of ethyl2-(5-bromo-N-ethyl-3-nitropicolinamido)acetate (1.0 equiv) in aceticacid (0.1 M) was added Fe (10 equiv) the mixture was heated to 80° C.and stirred for 1 h. The reaction was cooled to room temperature andfiltered through a short plug of Celite, washing with EtOAc and MeOH,and then concentrated. The resulting residue was suspended in DCM/MeOHand filtered, washing with both DCM and methanol. After concentratingagain, the residue was taken up in DCM and poured onto 1:1 saturatedaqueous NaHCO₃/brine. The mixture was extracted twice with DCM and thenonce with 30% i-PrOH/CHCl₃, and the combined organics were dried overMgSO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography over silica gel (DCM and 0-15% MeOH gradient) togive8-bromo-4-ethyl-3,4-dihydro-1H-pyrido[3,2-e][1,4]diazepine-2,5-dione asa white solid in 85% yield. LCMS (m/z) (M+H)=284.0/286.0, Rt=0.47 min.

Step 5:

To a stirred solution of8-bromo-4-ethyl-3,4-dihydro-1H-pyrido[3,2-e][1,4]diazepine-2,5-dione(1.0 equiv) in dioxane (0.08 M) at RT was added Lawesson's reagent (0.5equiv) and the mixture was heated to 65° C. and stirred for 1 h. Thereaction was concentrated and purified by flash column chromatographyover silica gel (heptane and 0-100% EtOAc gradient) to give8-bromo-4-ethyl-2-thioxo-3,4-dihydro-1H-pyrido[3,2-e][1,4]diazepin-5(2H)-oneas a white solid in 86% yield. LCMS (m/z) (M+H)=299.9/301.9, Rt=0.84min.

Step 6:

To a stirred solution of8-bromo-4-ethyl-2-thioxo-3,4-dihydro-1H-pyrido[3,2-e][1,4]diazepin-5(2H)-one(1.0 equiv) in n-butanol (0.1 M) at RT was added formic acid hydrazide(1.5 equiv) and the mixture was heated to 90° C. and stirred for 48 h.The reaction was diluted with DCM, concentrated, and purified by flashcolumn chromatography over silica gel (DCM and 0-35% MeOH gradient) toprovide9-bromo-5-ethyl-4H-pyrido[2,3-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6(5H)-oneas a yellow oil in 72% yield. LCMS (m/z) (M+H)=308.1/310.1, Rt=0.44 min.

Syntheses of10-bromo-7-ethyl-11b-methyl-1,4,7,11b-tetrahydro-[1,3]oxazino[3,4-c]quinazolin-6(2H)-one“Peak 1” and10-bromo-7-ethyl-11b-methyl-1,4,7,11b-tetrahydro-[1,3]oxazino[3,4-c]quinazolin-6(2H)-one“Peak 2”

Step 1:

To a stirred solution of 5-bromo-2-fluoropyridine (1.0 equiv) in DMF(0.5 M) were added ethyl amine (2 M in THF, 1.2 equiv) and K₂CO₃ (1.5equiv) and the mixture was heated at 115° C. overnight. The mixture waspoured onto water and extracted three times with ethyl acetate. Thecombined organics were washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated. The residue was purified by flashcolumn chromatography over silica gel (heptane and 0-30% EtOAc gradient)to provide 1-(5-bromo-2-(ethylamino)phenyl)ethanone as a yellow solid in82% yield. LCMS (m/z) (M+H)=242.0/244.0, Rt=1.21.

Step 2:

To a stirred solution of 1-(5-bromo-2-(ethylamino)phenyl)ethanone (1.0equiv) in acetic acid (0.18 M) at 25° C. was added sodium cyanate (1.5equiv) and the reaction was stirred for 48 h. The mixture was pouredonto water and extracted three times with ethyl acetate. The combinedorganics were washed with water and brine, dried over magnesium sulfate,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togive 6-bromo-1-ethyl-4-methylquinazolin-2(1H)-one as a pale yellow solidin 17% yield. LCMS (m/z) (M+H)=266.9/268.9, Rt=0.76 min.

Step 3:

To a stirred solution of 6-bromo-1-ethyl-4-methylquinazolin-2(1H)-one(1.0 equiv) in THF (0.16 M) at 0° C. was slowly added allylmagnesiumbromide (1 M in Et₂O, 1.7 equiv) and the reaction was allowed to warm toRT and stirred overnight. The mixture was poured onto 1 M citric acidand extracted three times with ethyl acetate. The combined organics weredried over magnesium sulfate, filtered, and concentrated. The residuewas purified by flash column chromatography over silica gel (heptane and0-100% EtOAc gradient) to provide4-allyl-6-bromo-1-ethyl-4-methyl-3,4-dihydroquinazolin-2(1H)-one as abright yellow solid in 53% yield. LCMS (m/z) (M+H)=309.0/311.0, Rt=1.10min. ¹H NMR (400 MHz, Chloroform-d) δ 7.35 (dd, J=8.7, 2.3 Hz, 1H), 7.24(d, J=2.3 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.67 (ddt, J=17.4, 10.2, 7.4Hz, 1H), 5.20 (s, 1H), 5.16-5.04 (m, 2H), 3.92 (qd, J=7.2, 3.9 Hz, 2H),2.42 (qd, J=13.7, 7.4 Hz, 2H), 1.49 (s, 3H), 1.23 (t, J=7.1 Hz, 3H).

Step 4:

O₃ was bubbled through a stirred solution of4-allyl-6-bromo-1-ethyl-4-methyl-3,4-dihydroquinazolin-2(1H)-one (1.0equiv) in 4:1 DCM/MeOH (0.03 M) at −78° C. until a persistent blue-greycolor was observed (about 3 min). The reaction mixture was then purgedwith N₂; NaBH₄ (10 equiv) was added, and the mixture was allowed to warmto RT and stirred for 15 min. The mixture was concentrated andpartitioned between EtOAc and 1 M citric acid. The aqueous layer wasextracted twice more with ethyl acetate, and the combined organics werewashed with water and brine, dried over magnesium sulfate, filtered, andconcentrated. The so-obtained pale yellow foam was used as6-bromo-1-ethyl-4-(2-hydroxyethyl)-4-methyl-3,4-dihydroquinazolin-2(1H)-onewithout further purification. LCMS (m/z) (M+H)=313.0/315.0, Rt=0.83 min.

Step 5:

A mixture of6-bromo-1-ethyl-4-(2-hydroxyethyl)-4-methyl-3,4-dihydroquinazolin-2(1H)-one(1.0 equiv) in formic acid (70 equiv) and formaldehyde (37% in water, 35equiv) was heated at 100° C. for 1 h. The mixture was cooled, basifiedwith 10% Na₂CO₃, and concentrated to remove excess formic acid andformaldehyde. The remaining aqueous mixture was extracted three timeswith ethyl acetate, and the combined organics were washed with water andbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash column chromatography over silica gel(heptane and 0-75% EtOAc gradient) to give the racemic product. This wasfurther purified by chiral SFC (IA 4.6×100 mm column, 5-55% MeOH in CO₂eluent). The first eluting peak afforded10-bromo-7-ethyl-11b-methyl-1,4,7,11b-tetrahydro-[1,3]oxazino[3,4-c]quinazolin-6(2H)-one“Peak 1” as a colorless oil in 41% yield. The second peak afforded10-bromo-7-ethyl-11b-methyl-1,4,7,11b-tetrahydro-[1,3]oxazino[3,4-c]quinazolin-6(2H)-one“Peak 2” as a colorless oil in 37% yield. NMR and LCMS data for eachenantiomer were identical. LCMS (m/z) (M+H)=325.0/327.0, Rt=1.05 min. ¹HNMR (400 MHz, Chloroform-d) δ 7.36 (dd, J=8.7, 2.3 Hz, 1H), 7.19 (d,J=2.3 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 5.71-5.66 (m, 1H), 4.55 (d,J=10.1 Hz, 1H), 4.19-4.11 (m, 1H), 4.00 (dq, J=14.2, 7.1 Hz, 1H),3.95-3.88 (m, 1H), 3.83 (dt, J=14.2, 7.1 Hz, 1H), 2.29 (td, J=13.1, 5.2Hz, 1H), 1.95 (dt, J=13.2, 1.9 Hz, 1H), 1.53-1.47 (m, 3H), 1.25 (t,J=7.1 Hz, 3H).

Synthesis of(rac)-(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-oneand(rac)-(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one

Step 1:

To a solution of 4-oxotetrahydropyran (1.0 equiv) in Et₂O (0.25 M) at−30° C. were added separately but simultaneously solutions of ethyldiazoacetate (1.3 equiv) and BF₃.OEt₂ (1.0 equiv), each in Et₂O (4 M)dropwise over 25 min. The mixture was allowed to stir at −30° C. for 1 hand then warmed to RT. The reaction was slowly quenched with 30% K₂CO₃and the phases were separated. The aqueous layer was extracted twicewith ethyl acetate, and the combined organics were dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-50% EtOAc gradient) toprovide ethyl 5-oxooxepane-4-carboxylate as a colorless oil in 90%yield. LCMS (m/z) Rt=0.87 min.

Step 2:

To a stirred solution of ethyl 5-oxooxepane-4-carboxylate (1.0 equiv) inTHF (0.4 M) at 25° C. was slowly added 60% NaH (1.3 equiv) and themixture was stirred for 2 h and then cooled to −78° C.N-phenyl-bis(trifluoromethanesulfonamide) (1.1 equiv) was then added andthe reaction was allowed to warm to RT and stirred overnight. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted twicewith EtOAc. The combined organics were dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography oversilica gel (heptanes with 0-30% ethyl acetate gradient) to give ethyl5-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydrooxepine-4-carboxylateas a colorless oil in 73% yield. ¹H NMR (400 MHz, Chloroform-d) δ 4.30(q, J=7.2 Hz, 2H), 3.85-3.76 (m, 4H), 2.86-2.74 (m, 4H), 1.36 (t, J=7.2Hz, 3H).

Step 3:

A stirred mixture of ethyl5-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydrooxepine-4-carboxylate(1.0 equiv), 5-bromo-2-fluoropyridine-3-boronic acid (1.05 equiv), andK₂CO₃ (2.5 equiv) in THF (0.2 M) was purged with N₂ for 5 min. Pd(Ph₃P)₄(0.05 equiv) was added, and the mixture was purged again for 5 min andthen heated at 65° C. for 2.5 h. The reaction was poured onto water andextracted twice with EtOAc The combined organics were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash column chromatography over silica gel (heptane with 0-30% ethylacetate gradient) to give ethyl5-(5-bromo-2-fluoropyridin-3-yl)-2,3,6,7-tetrahydrooxepine-4-carboxylateas a pale yellow oil in 74% yield. LCMS (m/z) (M+H)=344.0/346.0, Rt=1.04min. ¹H NMR (400 MHz, Chloroform-d) δ 8.17 (dd, J=2.4, 1.3 Hz, 1H), 7.60(dd, J=8.2, 2.5 Hz, 1H), 3.96 (q, J=7.1 Hz, 2H), 3.84-3.75 (m, 4H),2.96-2.86 (m, 2H), 2.78-2.70 (m, 2H), 0.96 (t, J=7.1 Hz, 3H).

Step 4:

N₂ was bubbled through a stirred solution of ethyl5-(5-bromo-2-fluoropyridin-3-yl)-2,3,6,7-tetrahydrooxepine-4-carboxylate(1.0 equiv), phenylsilane (4 equiv), and TBHP (5.5 M in decane, 4 equiv)in iPrOH (0.05 M) at RT for 20 min. Mn(dpm)₃ (0.1 equiv) was then addedand the mixture was further de-gassed for 30 sec more and then allowedto stir at RT for 22 h. The reaction mixture was concentrated andpurified by flash column chromatography over silica gel (heptane and0-50% EtOAc gradient) to give ethyl5-(5-bromo-2-fluoropyridin-3-yl)oxepane-4-carboxylate as adiastereomeric mixture in 83% yield. LCMS (m/z) (M+H)=346.1/348.1,Rt=1.02 and 1.05 min.

Step 5:

To a solution of ethyl5-(5-bromo-2-fluoropyridin-3-yl)oxepane-4-carboxylate (1.0 equiv) inDMSO (0.2 M) were added i-Pr₂NEt (4 equiv) and EtNH₂ (2 M in THF, 3.5equiv) and the mixture was heated at 130° C. for 72 h. The reaction wascooled to RT, poured onto half-saturated NH₄Cl, and extracted twice withEtOAc The combined organics were washed with water and brine, dried overMgSO₄, filtered, and concentrated. The crude material was purified byflash chromatography over silica gel (heptane with 0-50% ethyl acetategradient) to give(rac)-(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-oneas the earlier-eluting isomer as a colorless oil in 16% yield. LCMS(m/z) (M+H)=325.0/327.0, Rt=1.05 min. ¹H NMR (400 MHz, Chloroform-d) δ8.29 (dt, J=2.7, 1.4 Hz, 1H), 7.67-7.61 (m, 1H), 4.31-4.17 (m, 1H),4.16-4.04 (m, 1H), 4.00 (dd, J=4.5, 3.4 Hz, 1H), 3.97 (ddd, J=4.4, 3.3,1.4 Hz, 1H), 3.83-3.72 (m, 2H), 2.89-2.77 (m, 2H), 2.47 (ddd, J=13.9,9.3, 2.5 Hz, 1H), 2.39 (dtd, J=14.5, 4.6, 1.4 Hz, 1H), 2.12-2.00 (m,1H), 1.95 (dtd, J=14.2, 10.7, 3.1 Hz, 1H), 1.22 (t, J=7.0 Hz, 3H). Thelater-eluting isomer was isolated to give(rac)-(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-oneas a white solid in 22% yield. LCMS (m/z) (M+H)=325.0/327.0, Rt=1.02min. ¹H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J=2.3 Hz, 1H), 7.58-7.52(m, 1H), 4.26-4.16 (m, 1H), 4.16-4.05 (m, 1H), 3.90-3.66 (m, 4H), 3.16(ddd, J=10.4, 4.6, 3.0 Hz, 1H), 2.93 (q, J=4.7 Hz, 1H), 2.45 (dtd,J=14.9, 4.7, 3.4 Hz, 1H), 2.05 (dtd, J=15.9, 10.4, 5.5 Hz, 1H),1.93-1.80 (m, 1H), 1.69 (dq, J=15.1, 3.4 Hz, 1H), 1.20 (t, J=7.0 Hz,3H).

Syntheses of(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 1” and(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 2”

(rac)-(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-onewas subjected chiral SFC (IB 21×250 mm column, 10% i-PrOH in CO₂eluent). The first eluting peak afforded(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 1” as a white solid in 38% yield. The second peak afforded(5a,11b-cis)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 2” as a white solid in 40% yield. LCMS data for each enantiomerwere identical. LCMS (m/z) (M+H)=325.0/327.0, Rt=1.03 min.

Syntheses of(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 1” and(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 2”

(rac)-(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-onewas subjected chiral SFC (IC 21×250 mm column, 30% i-PrOH in CO₂eluent). The first eluting peak afforded(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 1” as a white solid in 32% yield. The second peak afforded(5a,11b-trans)-10-bromo-7-ethyl-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 2” as a white solid in 34% yield. LCMS data for each enantiomerwere identical. LCMS (m/z) (M+H)=325.0/327.0, Rt=1.05 min.

Syntheses of(4aR,10bS)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneand(4aS,10bR)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

Step 1:

To a stirred solution of tetrahydropyran-4-one (1.0 equiv) in toluene(0.5 M) at −78° C. was slowly added LiHMDS (1 M in THF, 1.1 equiv) andthe mixture was stirred for 30 min. Ethyl chloroformate (1.15 equiv) wasthen added and the reaction was allowed to warm to RT over 15 min. Thereaction was quenched by the addition of saturated aqueous NH₄Cl. Thelayers were separated; the organics were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography over silica gel (heptane with 0-40% ethyl acetategradient) to give ethyl 4-oxotetrahydro-2H-pyran-3-carboxylate, as acolorless oil in 18% yield. LCMS (m/z) (M+H)=344.0, Rt=1.13 min. ¹H NMR(400 MHz, Chloroform-d) δ 11.71 (s, 1H), 4.11 (t, J=1.7 Hz, 2H), 4.06(q, J=7.1 Hz, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.23 (tt, J=5.7, 1.7 Hz, 2H),1.13 (t, J=7.1 Hz, 3H).

Step 2:

To a stirred solution of ethyl 4-oxotetrahydro-2H-pyran-3-carboxylate(1.0 equiv) in THF (0.4 M) at 25° C. was slowly added 60% NaH (1.3equiv) and the mixture was stirred for 2 h and then cooled to −78° C.N-phenyl-bis(trifluoromethanesulfonamide) (1.1 equiv) was then added andthe reaction was allowed to warm to RT and stirred overnight. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted twicewith EtOAc. The combined organics were dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography oversilica gel (heptanes with 0-30% ethyl acetate gradient) to give ethyl4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate,as a light yellow oil in 122% yield. The excess yield is due tocontamination from phenyltriflamide byproducts. ¹H NMR (400 MHz,Chloroform-d) δ 4.45 (t, J=2.8 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 3.89 (t,J=5.5 Hz, 2H), 2.53 (tt, J=5.5, 2.7 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).

Step 3:

A stirred solution of4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate(1.0 equiv), 5-bromo-2-fluoropyridine-3-boronic acid (1.05 equiv), andK₂CO₃ (2.5 equiv) in THF (0.2 M) was purged with N₂ for 5 min. Pd(Ph₃P)₄(0.05 equiv) was added, and the mixture was purged again for 5 min andthen heated at 65° C. for 4 h. The reaction was poured onto water andextracted twice with EtOAc The combined organics were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was adsorbedon Celite and purified by flash column chromatography over silica gel(heptane with 0-30% ethyl acetate gradient) to give ethyl4-(5-bromo-2-fluoropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate as acolorless oil in 66% yield. LCMS (m/z) (M+H)=330.0/332.0, Rt=1.04 min.¹H NMR (400 MHz, Chloroform-d) δ 8.20 (dd, J=2.4, 1.4 Hz, 1H), 7.66 (dd,J=8.2, 2.5 Hz, 1H), 4.47 (t, J=2.8 Hz, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.90(t, J=5.5 Hz, 2H), 2.46 (tt, J=5.5, 2.8 Hz, 2H), 1.04 (t, J=7.1 Hz, 3H).

Step 4:

N₂ was bubbled through a stirred solution of ethyl4-(5-bromo-2-fluoropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate (1.0equiv), phenylsilane (4 equiv), and TBHP (5.5 M in decane, 4 equiv) ini-PrOH (0.07 M) at RT for 10 min. Mn(dpm)₃ (0.15 equiv) was then addedand the mixture was further de-gassed for 30 sec more and then allowedto stir at RT overnight. The reaction mixture was concentrated andpurified by flash column chromatography over silica gel (heptane and0-100% EtOAc gradient) to provide ethyl4-(5-bromo-2-fluoropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate as adiastereomeric mixture in 52% yield. LCMS (m/z) (M+H)=332.1/334.1,Rt=1.01 and 1.03 min.

Step 5:

To a solution of 4 ethyl4-(5-bromo-2-fluoropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate (1.0equiv) in DMSO (0.25 M) were added i-Pr₂NEt (4 equiv) and EtNH₂ (2 M inTHF, 3.5 equiv) and the mixture was heated at 120° C. overnight. Thereaction was cooled to RT, poured onto half-saturated NH₄Cl, andextracted twice with EtOAc The combined organics were washed with waterbrine, dried over MgSO₄, filtered, and concentrated. The crude materialwas purified by flash chromatography over silica gel (heptane with 0-30%ethyl acetate gradient) to give(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas the earlier-eluting isomer as a white solid in 36% yield. LCMS (m/z)(M+H)=311.0/313.0, Rt=1.04 min. ¹H NMR (400 MHz, Chloroform-d) δ 8.32(dd, J=2.3, 1.0 Hz, 1H), 7.53 (dd, J=2.2, 1.4 Hz, 1H), 4.51 (dd, J=11.9,4.6 Hz, 1H), 4.20 (dt, J=13.8, 6.9 Hz, 2H), 4.12-4.00 (m, 1H), 3.57-3.48(m, 2H), 2.86-2.75 (m, 1H), 2.38 (ddd, J=14.7, 10.5, 4.6 Hz, 1H), 2.17(ddd, J=11.2, 4.0, 2.0 Hz, 1H), 1.74 (qd, J=12.5, 4.6 Hz, 1H), 1.20 (t,J=7.0 Hz, 4H). The later-eluting isomer was isolated to giv(rac)-(4a,10b-cis)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white solid in 44% yield. LCMS (m/z) (M+H)=311.0/313.0, Rt=0.98min. 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.3 Hz, 1H), 7.56 (d,J=2.4 Hz, 1H), 4.77-4.68 (m, 1H), 4.33-4.21 (m, 1H), 4.19-4.09 (m, 1H),4.00 (ddd, J=11.5, 4.1, 2.3 Hz, 1H), 3.58-3.46 (m, 2H), 3.09 (dt,J=11.8, 5.1 Hz, 1H), 2.68-2.60 (m, 1H), 1.80-1.66 (m, 1H), 1.61 (d,J=2.8 Hz, 1H), 1.22 (t, J=7.0 Hz, 4H).

Step 6:

A stirred mixture of(rac)-(4a,10b-cis)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in EtOH (0.1 M) was gently heated with a heat gun until allsolid was in solution. To this was added NaOEt (21% in EtOH, 1.0 equiv)and the mixture was stirred for 3 h at RT. The mixture was concentrated,and the residue was partitioned between EtOAc and half-saturated NH₄Cl.The aqueous layer was extracted twice with EtOAc, and the combinedorganics were washed with water and brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash chromatography oversilica gel (heptane and 0-50% EtOAc gradient) to provide(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onein 38% yield along with recovered starting material in 58% yield. LCMS(m/z) (M+H)=310.9/312.9, Rt=1.04 min.

Step 7:

(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onewas subjected chiral SFC (ID 21×250 mm column, 15% MeOH in CO₂ eluent).The first eluting peak afforded(4aR,10bS)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white solid in 45% yield. The second peak afforded(4aS,10bR)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white solid in 46% yield. LCMS data for each enantiomer wereidentical. LCMS (m/z) (M+H)=311.0/313.0, Rt=1.04 min.

Syntheses of(4aR,10bS)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneand(4aS,10bR)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

Step 1:

Ethyl 4-(5-bromo-2-fluoropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate(1.0 equiv) was dissolved in DMSO (0.2 m). i-Pr₂NEt (5 equiv) and4-methoxybenzylamine (4.5 equiv) were added and the mixture was heatedat 130° C. for 48 h. The reaction was poured onto half-saturated NH₄C1and extracted twice with EtOAc The combined organics were washed withwater and brine dried over MgSO₄, filtered, and concentrated. Theresidue was and purified by flash column chromatography over silica gel(heptane and 0-50% EtOAc gradient). The less polar product peak provided(rac)-(4a,10b-trans)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a pale yellow solid in 38% yield. LCMS (m/z) (M+H)=403.1/405.1,Rt=1.20 min. ¹H NMR (400 MHz, Chloroform-d) δ 8.33 (dd, J=2.3, 1.0 Hz,1H), 7.52 (dd, J=2.2, 1.4 Hz, 1H), 7.38-7.31 (m, 2H), 6.84-6.75 (m, 2H),5.33-5.17 (m, 2H), 4.51 (dd, J=11.9, 4.6 Hz, 1H), 4.18 (dd, J=11.7, 3.9Hz, 1H), 3.76 (s, 3H), 3.59-3.46 (m, 2H), 2.87-2.73 (m, 1H), 2.43 (ddd,J=14.7, 10.5, 4.6 Hz, 1H), 2.24-2.07 (m, 1H), 1.74 (qd, J=12.4, 4.6 Hz,1H).

The more polar product peak gave(rac)-(4a,10b-cis)9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a pale yellow foam in 41% yield. LCMS (m/z) (M+H)=403.1/405.1,Rt=1.16 min.

Step 2:

To a stirred mixture of(rac)-(4a,10b-cis)9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in EtOH (0.2 M) was added NaOEt (21% in EtOH, 1.0 equiv) andthe mixture was stirred overnight at RT. The mixture was concentrated,and the residue was partitioned between EtOAc and half-saturated NH₄Cl.The aqueous layer was extracted twice with EtOAc, and the combinedorganics were washed with water and brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-50% EtOAc gradient) toprovide(rac)-(4a,10b-trans)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onein 66%. LCMS (m/z) (M+H)=403.1/405.1, Rt=1.20 min.

Step 3:

(rac)-(4a,10b-trans)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onewas subjected chiral SFC (ID 21×250 mm column, 30% MeOH in CO₂containing 10 mM NH₄OH eluent). The first eluting peak afforded(4aR,10bS)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white foam in 40% yield. The second peak afforded(4aS,10bR)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white foam in 42% yield. LCMS data for each enantiomer wereidentical. LCMS (m/z) (M+H)=403.1/405.1, Rt=1.20 min.

Step 4:

To a stirred solution of(4aS,10bR)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DCM (0.1 M) was slowly added triflic acid (6.5 equiv) andthe mixture was stirred at 25° C. for 2 h. The reaction was concentratedto remove most of the DCM, diluted with water and saturated aqueousNa₂CO₃ was added to basify the mixture. The heterogeneous mixture wasstirred for 5 min and then filtered, washing with water, Et₂O, andheptane. The so-obtained solid was dried under vacuum overnight to givean off-white solid The filtrate was poured into a separatory funnel andextracted three times with 30% i-PrOH/CHCl₃. The combined organics weredried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash column chromatography over silica gel (DCM and 0-100% EtOAcgradient). Product isolated was combined with the previously isolatedsolid to provide(4aS,10bR)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white solid in quantitative yield. In an analogous manner,(4aR,10bS)-9-bromo-6-(4-methoxybenzyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneprovided(4aR,10bS)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onein quantitative yield. The LCMS and NMR spectra of the two enantiomerswere identical. LCMS (m/z) (M+H)=283.0/285.0, Rt=0.70. ¹H NMR (400 MHz,DMSO-d6) δ 10.81 (s, 1H), 8.37-8.15 (m, 1H), 7.76 (s, 1H), 4.20 (dd,J=11.4, 4.4 Hz, 1H), 4.02 (dd, J=11.4, 3.5 Hz, 1H), 3.47-3.36 (m, 2H),3.03-2.89 (m, 1H), 2.42 (ddd, J=14.6, 10.6, 4.4 Hz, 1H), 2.28 (d, J=11.4Hz, 1H), 1.54 (qd, J=12.4, 4.5 Hz, 1H).

Synthesis of(4aS,10bR)-9-bromo-6-(2-hydroxyethyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

Step 1:

To a stirred solution of(4aS,10bR)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DMF (0.1 M) at 25° C. were added Cs₂CO₃ (6 equiv) and(2-bromoethoxy)-tert-butyldimethylsilane (3 equiv) and the reaction wasstirred for 4.5 h. The mixture was poured onto water and extracted threetimes with ethyl acetate. The combined organics were washed with waterand brine, dried over magnesium sulfate, filtered, and concentrated. Theresidue purified by flash chromatography over silica gel (heptane and0-40% EtOAc gradient) to give(4aS,10bR)-9-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a white crystalline solid in 63% yield. LCMS (m/z) (M+H)=441.3/443.3,Rt=1.57 min

Step 2:

To a stirred solution of(4aS,10bR)-9-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DCM (0.05 M) at 25° C. was added TfOH (1.5 equiv) and thereaction was stirred for 1 h. The mixture was partitioned between DCMand saturated aqueous NaHCO₃ and extracted three times with DCM. Thecombined organics were washed with brine, dried over magnesium sulfate,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) toprovide(4aS,10bR)-9-bromo-6-(2-hydroxyethyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a colorless oil in 80% yield. LCMS (m/z) (M+H)=327.1/329.1, Rt=0.79min

Synthesis of(4aS,10bR)-9-bromo-6-isopropyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

To a stirred solution of(4aS,10bR)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DMF (0.1 M) at 25° C. were added Cs₂CO₃ (3 equiv) and2-iodopropane (2.0 equiv) and the reaction was stirred for 4.5 h. Themixture was poured onto water and extracted three times with ethylacetate. The combined organics were washed with water and brine, driedover magnesium sulfate, filtered, and concentrated. The so-obtainedresidue was used as(4aS,10bR)-9-bromo-6-isopropyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onewithout further purification. LCMS (m/z) (M+H)=325.0/327.0, Rt=1.17 min.

Synthesis of(4aS,10bR)-9-bromo-6-(2,2-difluoroethyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

To a stirred solution of(4aS,10bR)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DMF (0.1 M) at 25° C. were added Cs₂CO₃ (3 equiv) and2-iodopropane (2.0 equiv) and the reaction was stirred for 4 h. Themixture was poured onto water and extracted three times with ethylacetate. The combined organics were washed with water and brine, driedover magnesium sulfate, filtered, and concentrated. The so-obtainedresidue was used as(4aS,10bR)-9-bromo-6-(2,2-difluoroethyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-onewithout further purification. LCMS (m/z) (M+H)=347.0/349.0, Rt=1.04 min.

Synthesis of(4aS,10bR)-9-bromo-6-(2-hydroxy-2-methylpropyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

To a stirred solution of(4aS,10bR)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DMF (0.15 M) at 25° C. were added Cs₂CO₃ (10 equiv),1-chloro-2-methyl-2-propanol (7 equiv) and NaI (0.1 equiv) and thereaction was heated to 100° C. and stirred for 72 h. The mixture waspoured onto water and extracted three times with ethyl acetate. Thecombined organics were washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated. The residue was purified by flashcolumn chromatography over silica gel (heptane and 0-100% EtOAcgradient) to give(4aS,10bR)-9-bromo-6-(2-hydroxy-2-methylpropyl)-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a pale yellow solid in 22% yield LCMS (m/z) (M+H)=355.1/357.1,Rt=0.86 min.

Synthesis of(4aR,10bR)-9-bromo-6-ethyl-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridine

To a stirred solution of(4aS,10bR)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in THF (0.2 M) at 25° C. was added BH₃.THF (1.0 M in THF, 3equiv) and 2-iodopropane (2.0 equiv) and the reaction was heated to 60°C. stirred overnight. The reaction was quenched with MeOH, stirred for 5min, and then and concentrated. The so-obtained residue was purified byflash column chromatography over silica gel (heptane and 0-100% EtOAcgradient) to give(4aR,10bR)-9-bromo-6-ethyl-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridineas a white solid in 96% yield. LCMS (m/z) (M+H)=297.0/299.0, Rt=0.71min.

Synthesis of(R)-10-chloro-7-(2-hydroxy-2-methylpropyl)-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one

To a stirred solution(R)-10-chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-onein DMF (0.15 M) at 25° C. were added Cs₂CO₃ (5 equiv) and isobutyleneoxide (3.5 equiv) and the reaction was heated to 100° C. and stirred for48 h. The mixture was poured onto water and extracted three times withethyl acetate. The combined organics were washed with water and brine,dried over magnesium sulfate, filtered, and concentrated. The residuewas purified by flash column chromatography over silica gel (heptane and0-100% EtOAc gradient) to give(R)-10-chloro-7-(2-hydroxy-2-methylpropyl)-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-oneas a yellow oil in 70% yield LCMS (m/z) (M+H)=326.8, Rt=0.75 min.

Syntheses of11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 1” and11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 2”

Step 1:

1,4-Oxazepan-5-one (1 equiv) was dissolved into anhydrous DCM (0.98 M)with stirring. Triethyloxonium tetrafluoroborate (1 equiv) was added inseveral portions and the reaction was allowed to stir at 23° C. After 16hr the reaction was shaken vigorously with saturated aqueous NaHCO₃until the effervescence subsided. The organic layer was washed withbrine and dried over anhydrous granular Na₂SO₄ then filtered andevaporated to yield a tan oily 5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepinein 89% yield. ¹H NMR (400 MHz, Chloroform-d) δ 4.04 (q, J=7.1 Hz, 2H),3.75-3.71 (m, 2H), 3.71-3.65 (m, 2H), 3.60-3.55 (m, 2H), 2.77-2.60 (m,2H), 1.29 (t, J=7.1 Hz, 3H).

Step 2:

5-Ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine (1 equiv) was dissolved intoanhydrous benzene (1 M) with 2,2-dimethyl-1,3-dioxane-4,6-dione (1equiv) and triethylamine (0.2 equiv) in a round bottom flask then heatedto reflux with reflux condenser under an atmosphere of nitrogen. After16 hr starting material had been consumed volatiles were removed and thecrude oily 2,2-dimethyl-5-(1,4-oxazepan-5-ylidene)-1,3-dioxane-4,6-dioneformed in 85% yield used as-is in the next step.

Step 3:

2,2-Dimethyl-5-(1,4-oxazepan-5-ylidene)-1,3-dioxane-4,6-dione (1 equiv)was dissolved into anhydrous MeoH (0.3 M) in a round bottom flask withreflux condenser and treated with sodium methoxide (3 equiv) added inone portion. The mixture was then heated to reflux with stirring under anitrogen atmosphere. After three hours the volatiles were removed andthe residue taken up into saturated ammonium chloride solution. The pHwas further adjusted to ˜7 with the addition of 6N HCl. The yellowsolution was extracted with DCM three times. The organics were combined,washed with brine and dried over anhydrous Na₂SO₄ then filtered andevaporated to yield a crude yellow oily methyl2-(1,4-oxazepan-5-ylidene)acetate which was used as-is in furtherchemistry. LCMS (m/z) (M+H)=172.0, Rt=0.74 min.

Step 4:

Methyl 2-(1,4-oxazepan-5-ylidene)acetate (1 equiv) was dissolved into a25% mixture of acetic acid in dioxane (0.3 M). This solution was treatedwith sodium borohydride (1 equiv) portionwise. Initial yellow colorfades slightly upon addition and as reaction progresses. After 30 minthe reaction was filtered and evaporated to yield an oil which was takenup into a 50:50 mixture of THF and saturated NaHCO₃ (0.3 M) then treatedwith benzyl carbonochloridate (1 equiv) and allowed to stir vigorouslyovernight. After 16 hr the reaction was diluted with EtOAc and thelayers separated. The organic layer was washed with brine and dried withNa₂SO₄. Volatiles were removed to yield a colorless crude oil which waspurified by flash column chromatography over silica gel (heptane with0-35% ethyl acetate gradient). Fractions containing desired product werecombined and evaporated to yield a colorless oily benzyl5-(2-methoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate in 39.4% yield. ¹HNMR (400 MHz, Chloroform-d) δ 7.45-7.31 (m, 5H), 5.23-5.12 (m, 2H), 4.54(ddq, J=19.7, 12.2, 6.5 Hz, 1H), 4.04-3.81 (m, 3H), 3.64 (d, J=18.8 Hz,3H), 3.57-3.33 (m, 2H), 3.26-3.09 (m, 1H), 2.63 (ddd, J=14.7, 11.2, 5.9Hz, 1H), 2.49 (td, J=14.7, 7.6 Hz, 1H), 2.26 (ddt, J=15.6, 12.4, 6.5 Hz,1H), 1.92-1.76 (m, 1H). LCMS (m/z) (M+H)=308.3, Rt=0.98 min.

Step 5:

Benzyl 5-(2-methoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate (1 equiv)was dissolved into a 1:1 mixture of ethyl acetate and methanol (0.102 M)in a round bottom flask with stir bar. The reaction was purged of oxygenby evacuating and purging up with nitrogen. 10% Palladium on carbon (0.1equiv) was added in one portion and the flask evacuated. The atmospherewas replaced with hydrogen from a balloon source (1 atm) and stirredvigorously. After 2 hours the was diluted with DCM and celite was addedto aggregate the palladium on carbon. The reaction was carefullyfiltered through a pad of celite such that the filter cake never becamedry. The filtrate was evaporated to yield a clear oily methyl2-(1,4-oxazepan-5-yl)acetate in 93% yield which was pure enough to useas-is in further chemistry. ¹H NMR (400 MHz, Chloroform-d) δ 3.89-3.74(m, 3H), 3.72 (s, 3H), 3.33 (dtt, J=7.7, 5.6, 4.2 Hz, 1H), 3.06 (ddd,J=14.4, 4.3, 3.4 Hz, 1H), 2.94 (ddd, J=14.4, 8.7, 3.5 Hz, 1H), 2.49 (dd,J=6.7, 3.2 Hz, 2H), 2.09-2.02 (m, 2H), 2.02-1.93 (m, 1H), 1.72 (dddd,J=14.5, 9.5, 8.3, 4.4 Hz, 1H).

Step 6:

5-Chloro-3-fluoro-2-nitropyridine (1 equiv) was dissolved into ofanhydrous DMF (0.182 M) along with methyl 2-(1,4-oxazepan-5-yl)acetate(1.1 equiv) and triethylamine (3 equiv). The mixture was heated to 80°C. under an atmosphere of nitrogen with reflux condenser and stirringovernight. After 16 hours the reaction was poured into H₂O and extractedthree times with EtOAc. Organics were combined, washed with brine, anddried anhydrous Na₂SO₄. The volatiles were removed and the residue waspurified by flash column chromatography over silica gel, eluting withheptane and 0-40% EtOAc gradient to give a yellow oil methyl2-(4-(5-chloro-2-nitropyridin-3-yl)-1,4-oxazepan-5-yl)acetate in 54.4%yield. LCMS (m/z) (M+H)=330.1, Rt=0.91 min.

Step 7:

Methyl 2-(4-(5-chloro-2-nitropyridin-3-yl)-1,4-oxazepan-5-yl)acetate (1equiv) was dissolved into 11 ml of glacial acetic acid along with irondust (10 equiv) in a round bottom flask with magnetic stirring andreflux condenser. The reaction was heated to 80° C. whereupon itdarkened and eventually an off-white suspension formed. The reaction washeated to 110° C. and left to for 16 hours, and then diluted into EtOAcand filtered through Celite. The filter cake was washed with EtOAc andDCM. The filtrate was evaporated and the residue partitioned betweensaturated aqueous NaHCO₃ and EtOAc to remove leftover acetic acid. Theorganic layer was washed with brine, dried over Na₂SO₄ then evaporatedto yield a tan solid which was purified by flash column chromatographyover silica gel (heptane with 40-80% ethyl acetate gradient) to give(rac)-11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one as off white crystals in 63.3%yield.(rac)-11-Chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-onewas subjected to chiral SFC (Whelk-O1 RR 21×250 mm column, 30% IPA inCO₂ eluent). The first eluting peak afforded11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 1” as a white solid in 19.5% yield. The second eluting peakafforded11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 2” as a white solid in 19.5% yield. NMR and LCMS data for eachenantiomer matched that of the racemate.

Synthesis of11-chloro-8-ethyl-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one

A vial was charged with11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 1” (1 equivalent) dissolved into anhydrous DMF (0.1 M) and treatedwith Cs₂CO₃ (1.5 equivalent) and ethyl iodide (1.25 equivalent). Thereaction was allowed to stir at room temperature for 16 hrs. Thereaction was poured into water and extracted three times with EtOAc. Theorganics were combined and washed with brine and dried over Na₂SO₄. Thevolatiles were removed to yield a clear light tan oily11-chloro-8-ethyl-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one(single enantiomer, from Peak 1) in 87% yield which was of sufficientpurity to carry on as-is. LCMS (m/z) (M+H)=296.1, Rt=0.88 min.

In a similar fashion,11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 2” was transformed to yield11-chloro-8-ethyl-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one(single enantiomer, from Peak 2). The analytics of both enantiomers wereidentical.

Synthesis of11-chloro-8-(2-hydroxyethyl)-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one

Step 1:

11-Chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“single enantiomer, Peak 1” (1 equiv) was dissolved into anhydrous DMF(0.1 M) and treated with Cs₂CO₃ (1.5 equiv) and(2-bromoethoxy)(tert-butyl)dimethylsilane (1.25 equiv). The reaction wasallowed to stir at room temperature for 1 hr whereupon sodium iodide(0.25 equiv) was added and the reaction was warmed to 55° C. using anoil bath overnight. After 16 hr the reaction was poured into H₂O andextracted three times with EtOAc. Organics were combined and dried withbrine followed by Na₂SO₄. Volatiles were removed to yield a clear lighttan oily 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one(single enantiomer, from Peak 1) in 83% yield which was of sufficientpurity to carry on to further chemistry. LCMS (m/z) (M+H)=426.3,R_(t)=1.48 min.

Step 2:

8-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one(1 equiv) was dissolved into anhydrous THF (0.111 M) and treated withTBAF in THF (1 M, 3 equiv). The reaction was allowed to stir at roomtemperature for 16 hr whereupon the volatiles were removed and theresidue was purified by flash column chromatography over silica gel,eluting with heptane and 0-85% EtOAc gradient, to give11-chloro-8-(2-hydroxyethyl)-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one (singleenantiomer, from Peak 1) in 74% yield. LCMS (m/z) (M+H)=312.1,R_(t)=0.67 min.

In a similar fashion,11-chloro-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one“Peak 2” was transformed to yield11-chloro-8-(2-hydroxyethyl)-1,2,4,5,5a,6-hexahydropyrido[3′,2′:2,3][1,4]diazepino[1,7-d][1,4]oxazepin-7(8H)-one(single enantiomer, from Peak 2). The analytics for both enantiomerswere identical.

Synthesis of(R)-10-chloro-7-ethyl-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one

Step 1:

(R)-Methyl 2-(morpholin-3-yl)acetate (1.1 equiv) was dissolved intoanhydrous DMF (0.206 M) along with 5-chloro-3-fluoro-2-nitropyridine (1equiv) and TEA (3 equiv). This mixture was heated to 80° C. for 72 hoursand then poured into water and extracted three times with EtOAc. Thecombined organics were washed with brine, dried over Na₂SO₄, and thevolatiles were removed to yield a deep red oil which was taken up into a1:1 mixture of AcOH:dioxane (0.139 M) and treated with iron dust (10equiv). The reaction was then heated to 110° C. with reflux condenserand stirring. After 16 hr the reaction was filtered to remove excessiron and the volatiles removed. The residue was partitioned betweenEtOAc and sat aq NaHCO₃. The organic layer was washed with brine anddried over Na₂SO₄ then filtered. The volatiles were removed to yield(R)-10-chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-onein 31.9% yield which was used as-is in further chemistry. LCMS (m/z)(M+H)=254.0, R_(t)=0.61 min.

Step 2:

(R)-10-Chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(1 equiv) was dissolved into anhydrous DMF (0.197 M) and treated withcesium carbonate (2 equiv) and iodoethane (1.5 equiv). This mixture wasstirred at room temperature for 72 hours. After this period of time thereaction was poured into H₂O and extracted three times with EtOAc.Organics were washed with brine, dried over Na₂SO₄ and evaporated to acrude oily(R)-10-chloro-7-ethyl-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-onein 76% yield which was used as-is in further chemistry. LCMS (m/z)(M+H)=282.1, R_(t)=0.87 min.

Synthesis of(R)-10-Chloro-7-(2-hydroxyethyl)-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one

Step 1:

(R)-10-Chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(1 equiv) was dissolved into anhydrous DMF (0.197 M) and treated withcesium carbonate (1.2 equiv) and tert-butyl(2-iodoethoxy)dimethylsilane(1.1 equiv). This mixture was stirred at room temperature for 16 hoursand then was poured into H₂O and extracted three times with EtOAc.Organics were combined, washed with brine and dried with Na₂SO₄. Afterfiltration the volatiles were removed to yield a crude oil which waspurified by flash column chromatography over silica gel (heptane with0-65% ethyl acetate gradient) to give(R)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-10-chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-onein 81% yield. LCMS (m/z) (M+H)=412.3, R_(t)=1.42 min.

Step 2:

(R)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-10-chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(1 equiv) was dissolved into MeOH (0.112 M) and treated with 1.25 M HClin methanol (5 equiv). After 45 min the volatiles were removed and theresidue was partitioned between EtOAc and sat aq NaHCO₃. Organics werewashed with brine and dried with Na₂SO₄. The volatiles were removed andthe so-obtained residue was purified by flash column chromatography oversilica gel (heptane with 0-75% ethyl acetate gradient) to provide thedesired(R)-10-chloro-7-(2-hydroxyethyl)-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-onein 73.3% yield. LCMS (m/z) (M+H)=298.0, R_(t)=0.64 min.

Synthesis of(S)-10-chloro-7-ethyl-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one

(S)-10-Chloro-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-one(1 equiv) was dissolved into anhydrous DMF (0.066 M) and treated withcesium carbonate (2 equiv) and iodoethane (1.5 equiv). This mixture wasstirred at room temperature for 72 hours. After this period of time thereaction was poured into H₂O and extracted three times with EtOAc.Organics were combined, washed with brine, dried over Na₂SO₄ andevaporated to yield an oily(S)-10-chloro-7-ethyl-4,4a,5,7-tetrahydro-1H-[1,4]oxazino[4,3-d]pyrido[2,3-b][1,4]diazepin-6(2H)-onein 72.9% yield which was used as-is in further chemistry. LCMS (m/z)(M+H)=282.1, R_(t)=0.87 min.

Syntheses of(4a,11b-cis)-10-chloro-7-ethyl-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 1” and “Peak 2”

Step 1:

To a mixture of 3-bromo-5-chloropyridin-2-amine (1.0 equiv.),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.15 equiv.), K₃PO₄ (2 equiv.), and X-Phos Pd G2 (5 mol %) under anatmosphere of nitrogen was added degassed 1,4-dioxane/water (4:1, 0.2M), and the resulting suspension was heated to 60° C. and stirred for 5hours. The reaction mixture was diluted with ethyl acetate, MgSO₄ wasadded, and the suspension was filtered through a pad of celite, washingwith ethyl acetate. The residue was purified by flash columnchromatography over silica gel (heptane with 0-70% ethyl acetategradient) to afford5-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine as an off-whitesolid in 96% yield. LCMS (m/z) (M+H)=211.0, Rt=0.53 min. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.96 (d, J=2.53 Hz, 1H), 7.25 (d, J=2.53 Hz,1H), 5.98 (tt, J=2.91, 1.52 Hz, 1H), 4.45-4.77 (m, 2H), 4.31 (q, J=2.78Hz, 2H), 3.95 (t, J=5.43 Hz, 2H), 2.35-2.43 (m, 2H).

Step 2:

To a stirring solution of5-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine (1 equiv.) int-butanol/water (2:1, 0.21 M) was added NBS (0.8 equiv.) in 4 portionsover 10 minutes, and the resulting mixture was stirred at roomtemperature for 2 hours. Additional NBS (0.1 equiv.) was added in 1portion, and the mixture was stirred at room temperature for 30 minutes.To this mixture was added aqueous 2 M NaOH (3.18 equiv.), and themixture was stirred at room temperature for 1.5 hours. The reaction wastransferred to a separatory funnel containing sat. aq. sodiumthiosulfate and sat. aq. sodium bicarbonate (1:1) and extracted threetimes with ethyl acetate. The combined organic phases were dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified byflash chromatography over silica gel (heptane with 0-70% ethyl acetategradient) to afford(rac)-3-(3,7-dioxabicyclo[4.1.0]heptan-6-yl)-5-chloropyridin-2-amine in66% yield. LCMS (m/z) (M+H)=227.1, Rt=0.59 min. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.99 (d, J=2.45 Hz, 1H), 7.46 (d, J=2.45 Hz, 1H),5.13 (br s, 2H), 4.23 (dd, J=13.69, 3.30 Hz, 1H), 4.04 (d, J=13.82 Hz,1H), 3.55-3.71 (m, 2H), 3.37 (d, J=3.18 Hz, 1H), 2.23 (dd, J=6.54, 4.83Hz, 2H).

Step 3:

To a mixture of3-(3,7-dioxabicyclo[4.1.0]heptan-6-yl)-5-chloropyridin-2-amine (1equiv.) and 10% Pd/C (10 mol %) under an atmosphere of nitrogen wasadded methanol (0.18 M) and triethylamine (2.5 equiv.). Hydrogen wasintroduced via a balloon, and the reaction was stirred at roomtemperature under an atmosphere of hydrogen for 3.5 hours. The reactionwas put under an atmosphere of nitrogen, diluted with dichloromethane,and filtered through a pad of celite, washing extensively withdichloromethane. The crude product was purified by flash columnchromatography over silica (dichloromethane with 0-10% methanolgradient) to afford(rac)-4-(2-amino-5-chloropyridin-3-yl)tetrahydro-2H-pyran-3-ol as alight tan solid in 41% yield. LCMS (m/z) (M+H)=229.0, Rt=0.37 min. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=2.51 Hz, 1H), 7.52 (d,J=2.51 Hz, 1H), 4.39-5.30 (m, 2H), 4.17 (dd, J=11.54, 4.52 Hz, 1H), 4.06(dd, J=12.05, 2.01 Hz, 1H), 3.99 (s, 1H), 3.71 (dd, J=12.05, 1.00 Hz,1H), 3.61 (td, J=11.86, 2.13 Hz, 1H), 2.71-2.86 (m, 1H), 2.42 (qd,J=12.80, 4.52 Hz, 1H), 1.58 (br dd, J=13.55, 1.76 Hz, 1H).

Step 4:

To a mixture of(rac)-4-(2-amino-5-chloropyridin-3-yl)tetrahydro-2H-pyran-3-ol (1equiv.) and CDI (1.7 equiv.) in a round-bottom flask with a condenserunder an atmosphere of nitrogen was added acetonitrile (0.05 M), and themixture was heated to 60° C. and stirred for 16 hours. Additional CDI(0.1 equiv.) was added, and the mixture was stirred at 60° C. for 1hour. The reaction mixture was cooled to room temperature, and Sc(OTf)₃(10 mol %) was added in a single portion. The reaction mixture washeated to reflux and stirred for 24 hours. The reaction mixture wasconcentrated to approximately one-sixth of the initial volume andfiltered, washing with acetonitrile. The resulting white solid wasrecovered and dried in vacuo to afford(rac)-(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-onein 88% yield. LCMS (m/z) (M+H)=255.0, Rt=0.63 min. 1H NMR (400 MHz,DMSO-d6) δ ppm 9.92 (s, 1H), 8.23 (d, J=2.51 Hz, 1H), 7.91 (d, J=2.51Hz, 1H), 4.78 (s, 1H), 3.87-4.03 (m, 2H), 3.46-3.64 (m, 2H), 3.29-3.35(m, 1H), 1.92 (qd, J=12.55, 4.27 Hz, 1H), 1.73-1.85 (m, 1H).

Step 5:

To a stirring solution of(rac)-(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one(1 equiv.) in DMF (0.3 M) was added cesium carbonate (1.5 equiv.)followed by ethyl iodide (1.2 equiv.), and the resulting mixture wasstirred at room temperature for 3.5 hours. The reaction mixture wassuspended in ethyl acetate (10 mL), and extracted with 0.1 M aq. HCl (10mL) followed by brine (10 mL). The organic phase was dried over MgSO4,filtered, and concentrated in vacuo to afford(rac)-(4a,11b-cis)-10-chloro-7-ethyl-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-oneas a white solid in 92% yield. LCMS (m/z) (M+H)=283.0, Rt=0.92 min. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.36 (d, J=2.01 Hz, 1H), 7.58-7.67 (m,1H), 4.82 (ddd, J=8.28, 5.90, 4.14 Hz, 1H), 4.05-4.15 (m, 1H), 3.94-4.05(m, 1H), 3.82-3.91 (m, 3H), 3.38-3.49 (m, 2H), 2.22-2.31 (m, 1H),2.07-2.19 (m, 1H), 1.28 (t, J=7.03 Hz, 3H).

Step 6:

(rac)-(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-onewas purified by chiral SFC (ID 21×250 mm 5 um, 20% isopropanol in CO₂eluent). The first eluted peak afforded a single enantiomer of(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 1” as a white solid in 45% yield. The second eluted peak affordedthe opposite enantiomer of(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyran[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 2” as a white solid in 46% yield. The LCMS and ¹H NMR data for thetwo enantiomers matched, and matched the characterization data reportedfor the racemate.

Syntheses of(4a,11b-cis)-10-chloro-7-(4-methoxybenzyl)-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 1” and “Peak 2”

Step 1:

To a stirring suspension of(rac)-(4a5,11bR)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one(1 equiv.) and KI (5 mol %) in DMF (0.3 M) at room temperature was added4-methoxybenzyl chloride (1.05 equiv.), and the resulting mixture wasstirred for 18 hours. Additional 4-methoxybenzyl chloride (0.2 equiv.)was added, and the mixture was stirred for 3 hours. The reaction mixturewas diluted with ethyl acetate and washed with 0.1 M aq. HCl and brine.The organic phase was dried over MgSO₄, filtered, and concentrated invacuo to afford a yellow oil. The residue was purified by chiral SFC(OJ-H 21×250 mm, 20% MeOH in CO₂ eluent). The first eluted peak affordedone enantiomer of(4a,11b-cis)-10-chloro-7-(4-methoxybenzyl)-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 1” in 41% yield. The second eluted peak afforded the oppositeenantiomer of(4a,11b-cis)-10-chloro-7-(4-methoxybenzyl)-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 2” in 42% yield. The LCMS and ¹H NMR data for the two enantiomersmatched. LCMS (m/z) (M+H)=375.0, Rt=1.11 min. 1H NMR (400 MHz, DMSO-d6)δ ppm 8.41 (d, J=2.53 Hz, 1H), 7.94 (d, J=2.27 Hz, 1H), 7.22 (d, J=8.84Hz, 2H), 6.74-6.90 (m, 2H), 4.94-5.10 (m, 2H), 4.71-4.87 (m, 1H), 3.79(ddd, J=11.37, 7.07, 3.79 Hz, 1H), 3.69 (s, 3H), 3.51-3.67 (m, 3H),3.36-3.44 (m, 1H), 1.98 (dtd, J=14.49, 7.47, 7.47, 3.66 Hz, 1H),1.75-1.86 (m, 1H).

Synthesis of(4a,11b-cis)-10-chloro-7-(2-hydroxyethyl)-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“from Peak 1”

Step 1:

(4a,11b-cis)-10-Chloro-7-(4-methoxybenzyl)-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 1” (1 equiv) was dissolved into DCM (0.03 M) and treated withtrifluoromethanesulfonic acid (5 equiv) at 23° C. in a pressure relievedscrew cap vial. After stirring at RT for 15 min the reaction wasquenched carefully with saturated aqueous NaHCO₃. Reaction waspartitioned with 25% isopropanol in DCM. The organics were separated andwashed with brine followed by drying over anhydrous granular Na₂SO₄. Thevolatiles were removed to yield of an off-white(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-onein 130% yield (p-methoxybenzyl alcohol is the likely impurity). LCMS(m/z) (M+H)=255.1, R_(t)=0.64 min.

Step 2:

(4a,11b-cis)-10-Chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one(1 equiv) was dissolved into anhydrous DMF (0.098 M) along with cesiumcarbonate (5 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (3.5equiv) and sodium iodide (1 equiv). The reaction was heated to 60° C.and left to stir for 3 hr. It was then poured into H₂O and extractedthree times with EtOAc. Organics were combined, washed with brine, anddried over anhydrous granular Na₂SO₄. After decantation the volatileswere removed and the residue was purified by flash column chromatographyover silica gel (heptane with 0-40% ethyl acetate gradient) to give(4a,11b-cis)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-onein 81% yield. LCMS (m/z) (M+H)=413.2, R_(t)=1.81 min.

Step 3:

(4a,11b-cis)-7-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one(1 equiv) was dissolved into anhydrous MeOH (0.05 M) along with 1.25MHCl in methanol (5 equiv). Reaction was stirred for 2 hr and then thevolatiles were removed. The residue was partitioned between EtOAc andsaturated aqueous NaHCO₃. After the organic layer was washed with brine,dried over anhydrous granular Na₂SO₄ the volatiles were removed to yielda quite pure(4a,11b-cis)-10-chloro-7-(2-hydroxyethyl)-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“from Peak 1” in 71.8% yield which was used as-is in further chemistry.LCMS (m/z) (M+H)=299.1, R_(t)=0.68 min.

Synthesis of(4aR,11bR)-10-bromo-7-ethyl-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one

Step 1:

To a stirred solution of(4aR,10bS)-9-bromo-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in DCM (0.1 M) were added i-Pr₂NEt (4 equiv), Boc₂O (1.5equiv), and DMAP (0.2 equiv) and the mixture was heated to 50° C. andstirred overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl and extracted three times with EtOAc, and thecombined organics were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-40% EtOAc gradient) toprovide (4aR,10bS)-tert-butyl9-bromo-5-oxo-4,4a,5,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridine-6(2H)-carboxylatein 87% yield. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.33 (dd, J=2.15,0.88 Hz, 1H), 7.61 (dd, J=2.15, 1.39 Hz, 1H), 4.51 (dd, J=12.00, 4.42Hz, 1H), 4.21 (dd, J=11.75, 3.66 Hz, 1H), 3.45-3.62 (m, 2H), 2.87-3.05(m, 1H), 2.50 (ddd, J=14.34, 10.29, 4.42 Hz, 1H), 2.41-2.59 (m, 1H),2.16-2.28 (m, 1H), 1.77 (qd, J=12.29, 4.55 Hz, 1H), 1.52-1.63 (m, 9H).

Step 2:

To a stirred solution of (4aR,10bS)-tert-butyl9-bromo-5-oxo-4,4a,5,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridine-6(2H)-carboxylate(1.0 equiv) in THF (0.3 M) was added NaOH (2.5 equiv), and the mixturewas heated to 50° C. and stirred for 2 h. The volatiles were removedunder pressure, and the resulting residue was purified by HPLC (X-Bridge50×50 uM column, 5-20% MeCN in 5 mM aq NH₄OH gradient) to provide(3R,4R)-4-(5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylicacid in 97% yield as a 2:1 diastereomeric mixture which was used withoutfurther purification. LCMS (m/z) (M+H)=400.9/402.9, Rt=0.83 and 0.87 min

Step 3:

To a stirred solution of(3R,4R)-4-(5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylicacid (1.0 equiv) in DMF (0.12 M) at 25° C. were added Cs₂CO₃ (7.5 equiv)and iodoethane (15 equiv) and the reaction was heated to 50° C. andstirred for 5 h. The mixture was poured onto half-saturated aqueousNH₄Cl and extracted three times with ethyl acetate. The combinedorganics were dried over magnesium sulfate, filtered, and concentrated.The residue was purified by flash column chromatography over silica gel(heptane and 0-70% EtOAc) to give (3R,4S)-ethyl4-(5-bromo-2-((tert-butoxycarbonyl)(ethypamino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylateas a white solid in 73% yield. LCMS (m/z) (M+H)=457.0/459.0, Rt=1.30min.

Step 4:

To a stirred solution of (3R,4S)-ethyl4-(5-bromo-2-((tert-butoxycarbonyl)(ethyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate(1.0 equiv) in THF (0.16 M) was added NaOH (5 equiv) and the mixture washeated to 60° C. and stirred for 2 h. The volatiles were removed underreduced pressure and the resulting residue partitioned between saturatedaqueous NH₄Cl and EtOAc. The aqueous layer was extracted twice more withEtOAc, and the combined organic phases were washed with brine, driedover MgSO₄, filtered, and concentrated. The so-obtained white foam wasused as(3R,4S)-4-(5-bromo-2-((tert-butoxycarbonyl)(ethyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylicacid, obtained in 80% yield without further purification. LCMS (m/z)(M+H)=429.0/431.0, Rt=0.96 min.

Step 5:

An approximately 0.03 M stock solution of “dry mCPBA” was prepared. 70%mCPBA was dissolved in DCM (0.03 M) and washed with saturated aqueousNaHCO₃. The organics were dried over MgSO₄ and filtered. The so-obtainedsolution was used in the subsequent reaction.

To a stirred solution of(3R,4S)-4-(5-bromo-2-((tert-butoxycarbonyl)(ethyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylicacid (1.0 equiv) in DCM (0.2 M) at 0° C. were added DCC (1.3 equiv) and“dry mCPBA” (0.03 M in DCM, 1.3 equiv) and the reaction was stirred for2 h at 0° C. The reaction was filtered washing with DCM, andconcentrated. The so-obtained residue was purified by flash columnchromatography over silica gel (heptane and 0-60% EtOAc gradient) togive(3R,4S)-4-(5-bromo-2-((tert-butoxycarbonyl)(ethyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylic3-chlorobenzoic peroxyanhydride as a colorless oil in 69% yield. LCMS(m/z) (M+H-tBu)=527.1/529.1, Rt=1.42 mm.

Step 6:

A solution(3R,4S)-4-(5-bromo-2-((tert-butoxycarbonyl)(ethyl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxylic3-chlorobenzoic peroxyanhydride (1.0 equiv) in benzene (0.03 M) washeated to 80° C. and stirred overnight. The reaction mixture wasconcentrated and the residue was taken up in MeOH (0.05 M). K₂CO₃ (4equiv) was added, and the mixture was stirred at RT for 5 h. Thereaction was diluted with DCM, filtered, and concentrated. The residuewas purified by flash column chromatography over silica gel (heptane and0-60% EtOAc gradient) to give tert-butyl(5-bromo-3-((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)(ethyl)carbamateas a colorless oil in 49% yield. LCMS (m/z) (M+H-tBu)=345.1/347.1,Rt=1.00 min

Step 7:

To a solution of tert-butyl(5-bromo-3-((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)(ethyl)carbamate(1.0 equiv) in dioxane (0.1 M) at 25° C. was added HCl (4 M aq, 15equiv) and the mixture was stirred overnight. The reaction mixture wasconcentrated, and the residue was taken up in a mixture of EtOAc andsaturated aqueous Na₂CO₃ and stirred vigorously for 10 min. Afterpartitioning of the resulting mixture, the aqueous layer was extractedtwice more with EtOAc. The combined organics were washed with brine,dried over MgSO₄, filtered, and concentrated to(3R,4R)-4-(5-bromo-2-(ethylamino)pyridin-3-yl)tetrahydro-2H-pyran-3-olas a white solid in 93% yield which was used without furtherpurification. LCMS (m/z) (M+H)=301.1/303.1, Rt=0.51 min. ¹H NMR (400MHz, Chloroform-d) δ 8.03 (d, J=2.3 Hz, 1H), 7.44 (d, J=2.2 Hz, 1H),4.09 (dd, J=11.1, 4.9 Hz, 1H), 4.06-4.00 (m, 1H), 3.71 (td, J=10.0, 4.8Hz, 1H), 3.50-3.43 (m, 1H), 3.40 (q, J=7.2, 5.9 Hz, 2H), 3.29 (dd,J=10.9, 10.1 Hz, 1H), 2.64 (ddd, J=13.4, 10.1, 3.7 Hz, 1H), 1.98-1.86(m, 1H), 1.75 (ddd, J=11.8, 3.7, 1.9 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H). ¹HNMR (400 MHz, Methanol-d4) δ 7.90 (d, J=2.4 Hz, 1H), 7.50 (d, J=2.3 Hz,1H), 3.99 (dd, J=10.9, 4.8 Hz, 1H), 3.94 (dd, J=11.4, 3.8 Hz, 1H), 3.72(td, J=10.0, 4.8 Hz, 1H), 3.51 (td, J=11.7, 2.2 Hz, 1H), 3.36 (q, J=7.1Hz, 2H), 3.25-3.18 (m, 1H), 2.70 (ddd, J=12.1, 10.1, 3.9 Hz, 1H), 1.79(ddt, J=13.5, 3.6, 1.8 Hz, 1H), 1.72-1.61 (m, 1H), 1.21 (t, J=7.2 Hz,3H).

Step 8:

A mixture of(3R,4R)-4-(5-bromo-2-(ethylamino)pyridin-3-yl)tetrahydro-2H-pyran-3-ol(1.0 equiv) and CDI (1.8 equiv) under N₂ was taken up in acetonitrile(0.075 M) and heated at 60° C. was overnight. Scandiumtrifluoromethanesulfonate (0.2 equiv) was then added, and the reactionwas further heated to 105° C. stirred for 7 days. The reaction mixturewas concentrated in vacuo, transferred to a separatory funnel containinghalf-saturated aqueous ammonium chloride and extracted twice withdichloromethane. The combined organic extracts were dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-50% EtOAc gradient) toprovide((4aR,11bR)-10-bromo-7-ethyl-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-oneas a white solid in 61% yield. LCMS (m/z) (M+H)=327.1/329.1, Rt=0.92min. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (d, J=2.26 Hz, 1H), 7.64(dd, J=2.26, 0.75 Hz, 1H), 4.25 (dd, J=10.79, 4.52 Hz, 1H), 4.04-4.19(m, 3H), 3.96 (dq, J=13.80, 7.03 Hz, 1H), 3.48-3.62 (m, 2H), 2.85-3.01(m, 1H), 2.00-2.10 (m, 2H), 1.28 (t, J=7.03 Hz, 3H).

Synthesis of2-(1,1-difluoroethyl)-3-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide

Step 1:

To a stirring solution of 3-fluoro-4-methylpyridine (1 equiv.) in THF(0.1 M) under an atmosphere of nitrogen in a heat gun-dried flask at−78° C. (dry ice/acetone bath) was added 1.6 M nBuLi in hexanes (1.05equiv.), and the reaction mixture was stirred at −78° C. for 1.5 hours.To the reaction mixture at −78° C. was added acetaldehyde (1.05 equiv.)dropwise, and the reaction mixture was stirred at −78° C. for 1 hour.The reaction mixture was warmed to 0° C., stirred at this temperaturefor 5 minutes, then quenched via dropwise addition of water and allowedto gradually warm to room temperature. The reaction mixture wastransferred to a separatory funnel containing water and extracted threetimes with ethyl acetate. The combined organic extracts were dried overMgSO₄, filtered, and concentrated in vacuo to afford a clear oil. Thecrude product was purified by flash column chromatography over silica(heptane with 0-50% ethyl acetate gradient) to afford(rac)-1-(3-fluoro-4-methylpyridin-2-yl)ethanol as a white solid in 43%yield. LCMS (m/z) (M+H)=156.0, Rt=0.43 min. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.23 (d, J=4.80 Hz, 1H), 7.13 (t, J=5.31 Hz, 1H),5.11 (qd, J=6.53, 1.39 Hz, 1H), 4.12-4.77 (m, 1H), 2.36 (d, J=1.52 Hz,3H), 1.50 (dd, J=6.57, 1.01 Hz, 3H).

Step 2:

To a stirring solution of (rac)-1-(3-fluoro-4-methylpyridin-2-yl)ethanol(1 equiv.) in toluene (0.26 M) was added MnO₂ (3 equiv.), and thereaction mixture was heated to 110° C. and stirred for 16 hours. Thereaction mixture was diluted with dichloromethane, and filtered througha pad of celite, washing with dichloromethane. The filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography over silica (heptane with 0-30% ethyl acetate gradient)to afford 1-(3-fluoro-4-methylpyridin-2-yl)ethanone as a clear oil in80% yield. LCMS (m/z) (M+H)=154.1, Rt=0.65 min. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.35 (d, J=4.55 Hz, 1H), 7.31-7.42 (m, 1H), 2.72 (d,J=1.26 Hz, 3H), 2.39 (d, J=1.26 Hz, 3H).

Step 3:

To a stirring solution of 1-(3-fluoro-4-methylpyridin-2-yl)ethanone (1equiv.) in dichloromethane (0.5 M) and EtOH (1 mol %) under anatmosphere of nitrogen at 0° C. was added DAST (2.5 equiv.), and thereaction mixture was allowed to warm to room temperature and stirred for6 days. The reaction mixture was cooled to 0° C. and quenched with sat.aq. NaHCO₃ (approximately 60 equiv.) slowly at 0° C., then allowed towarm to room temperature and transferred to a separatory funnelcontaining dichloromethane. At this time, rapid gas formation was stillobserved following addition of a few drops of sat. aq. NaHCO₃. Themixture was transferred to an Erlenmeyer flask, diluted withdichloromethane, stirred, and sat. aq. NaHCO₃ was added slowly over 30minutes. The mixture was stirred for 1 hour at room temperature, afterwhich pH paper showed that the aqueous phase was basic (pH 8-9) and nogeneration of gas was observed following addition of additional NaHCO₃.The mixture was transferred to a separatory funnel, the layers wereseparated, and the aqueous phase was reextracted once withdichloromethane. The combined organic extracts were dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica (heptane with 0-30% ethyl acetategradient) to afford 2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine as ayellow oil in 42% yield. LCMS (m/z) (M+H)=176.1, Rt=0.87 min. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.29 (d, J=4.80 Hz, 1H), 7.23-7.33 (m,1H), 2.39 (d, J=2.02 Hz, 3H), 2.08 (t, J=18.82 Hz, 3H). ¹⁹F NMR (376MHz, CHLOROFORM-d) δ ppm −89.59 (d, J=19.50 Hz, 2F), −127.75 (br t,J=19.50 Hz, 1F).

Step 4:

To a solution of 2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine (1equiv.) in Water (0.38 M) was added KMnO₄ (3 equiv.) and the resultingmixture was heated to 80° C. and stirred for 6 hours. The reactionmixture was filtered through celite, washing with water and ethylacetate. The biphasic mixture was transferred to a separatory funnel andthe phases were separated. The aqueous phase was acidified with 1 M aq.HCl (approximately 0.5 equiv., difficult to determine exact pH due tothe purple color of the aqueous phase) and extracted three times withethyl acetate. The three post-acidification organic extracts werecombined, dried over MgSO₄, filtered, and concentrated in vacuo toafford 2-(1,1-difluoroethyl)-3-fluoroisonicotinic acid as a brown solidin 18% yield. LCMS (m/z) (M+H)=206.1, Rt=0.58 min. ¹H NMR (400 MHz,METHANOL-d4) δ ppm 8.51 (br d, J=3.79 Hz, 1H), 7.93 (br s, 1H), 2.06 (t,J=18.95 Hz, 3H). ¹⁹F NMR (376 MHz, METHANOL-d4) δ ppm −90.85 (d, J=19.50Hz), −124.31 (br s).

Step 5:

A mixture of4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.05equiv.), 2-(1,1-difluoroethyl)-3-fluoroisonicotinic acid (1 equiv.),EDC.HCl (1.05 equiv.), and 1-hydroxy-7-azabenzotriazole (1.05 equiv.)under an atmosphere of nitrogen was dissolved in DMF (0.49 M), and theresulting mixture stirred for 2.5 hours at room temperature. Thereaction was quenched with water, and the resulting precipitate wasfiltered, washing with water. The solid was dissolved in DCM andconcentrated in vacuo to afford2-(1,1-difluoroethyl)-3-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamideas a tan solid in 67% yield. LCMS (m/z) (M+H)=421.1, Rt=1.26 min. ¹HNMR(400 MHz, CHLOROFORM-d) δ ppm 8.59 (d, J=4.80 Hz, 1H), 8.35 (br d,J=13.14 Hz, 1H), 8.14 (t, J=5.05 Hz, 1H), 7.93 (dd, J=8.08, 2.53 Hz,1H), 7.71 (d, J=2.53 Hz, 1H), 7.19-7.25 (m, 1H), 2.45-2.60 (m, 3H), 2.15(t, J=18.95 Hz, 3H), 1.37 (s, 12H). 19F NMR (376 MHz, CHLOROFORM-d) δppm −88.97 (d, J=20.65 Hz), −125.58-−125.35 (m).

Synthesis ofN-(3-(8-ethyl-7-oxo-7,8-dihydro-1,8-naphthyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

To a stirred solution of 6-bromo-1,8-naphthyridin-2(1H)-one (1 equiv) inDMF (0.2 M) at 25° C. were added cesium carbonate (1.3 equiv) andiodoethane (1.1 equiv) and the reaction was stirred for 30 min. Themixture was poured onto water and extracted three times with ethylacetate. The combined organics were washed with water and brine, driedover MgSO₄, filtered, and concentrated to give6-bromo-1-ethyl-1,8-naphthyridin-2(1H)-one as a yellow solid in 87%yield, which was used without further purification. LCMS (m/z)(M+H)=253.0/255.0, Rt=0.91 min

Step 2:

To a stirred suspension of 6-bromo-1-ethyl-1,8-naphthyridin-2(1H)-one(1.0 equiv) andN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.05 equiv) in THF (0.2 M) flushed with nitrogen gas, was addedsequentially K₃PO₄ (0.5 M aq, 2 equiv) followed by XPhos Pd G2 catalyst(0.05 equiv) and XPhos (0.05 equiv). The resultant reaction mixture washeated at 45° C. for 45 min. The reaction was poured onto water andextracted twice with EtOAc, the combined organics were washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash column chromatography over silica gel, eluting withheptane and 0-100% EtOAc gradient to giveN-(3-(8-ethyl-7-oxo-7,8-dihydro-1,8-naphthyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a pale yellow solid in 84% yield. ¹H NMR (400 MHz, Methanol-d₄) δ8.91 (d, J=5.0 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.52 (s, 1H), 8.30 (s,1H), 8.18-8.10 (m, 2H), 7.99 (d, J=9.5 Hz, 1H), 7.76-7.64 (m, 2H), 7.38(d, J=8.2 Hz, 1H), 6.79 (d, J=9.5 Hz, 1H), 4.65 (q, J=7.0 Hz, 2H), 2.31(s, 3H), 1.36 (t, J=7.0 Hz, 3H). LCMS (m/z) (M+H)=453.3, Rt=1.18 min.

Syntheses of (6aS, 6bS, 9aS,9bS)-2-bromo-5-ethyl-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneand (6aR, 6bR, 9aR,9bR)-2-bromo-5-ethyl-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one

Step 1:

A mixture of 6-bromo-1,8-naphthyridin-2(1H)-one (1.0 equiv) and2,5-dihydrofuran (10 equiv) in AcOH (0.05 M) was irradiated with UVAlamps (Rayonet reactor, RPR3500 A bulbs) at RT overnight. The mixturewas filtered, washing with EtOAc, and the solids were dried in vacuo.The so-obtained residue was purified via flash chromatography oversilica gel, eluting with DCM and 0-20% EtOAc gradient to provide thetitle(rac)-2-bromo-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneas a yellow solid in 9% yield. ¹H NMR (400 MHz, DMSO-d6) δ 10.60 (s,1H), 8.20 (m, 1H), 7.85 (m, 1H), 4.13 (d, J=9.4 Hz, 1H), 3.97 (d, J=9.6Hz, 1H), 3.38 (m, 3H), 3.06 (d, J=8.9, 5.1 Hz, 1H), 2.90 (dd, J=9.7, 4.4Hz, 1H), 2.84 (m, 1H). LCMS (m/z) (M+H)=295.1/297.1, Rt=0.69 min.

Step 2:

To a stirred solution of(rac)-2-bromo-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one(1.0 equiv) in DMF (0.1 M) at 25° C. were added Cs₂CO₃ (2.0 equiv) andiodoethane (1.75 equiv) and the reaction was stirred for 3.5 h. Themixture was poured onto water and extracted three times with ethylacetate. The combined organics were washed with water and brine, driedover magnesium sulfate, filtered, and concentrated. The residue waspurified by flash column chromatography over silica gel (heptane and0-50% EtOAc) to give(rac)-2-bromo-5-ethyl-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneas a white solid in 68% yield. LCMS (m/z) (M+H)=323.0/325.0, Rt=0.99min.

Step 3:

(rac)-2-bromo-5-ethyl-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-onewas subjected chiral SFC (IB 21×250 mm column, 15% i-PrOH in CO₂eluent). The first eluting peak afforded (6aS, 6bS, 9aS,9bS-2-bromo-5-ethyl-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneas a white solid in 43% yield. The second peak afforded (6aR, 6bR, 9aR,9bR)-2-bromo-5-ethyl-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneasa white solid in 39% yield. LCMS data for each enantiomer wereidentical. LCMS (m/z) (M+H)=323.0/325.0, Rt=0.99 min.

Syntheses of:2-bromo-5-(2-hydroxyethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one“Peak 1” and2-bromo-5-(2-hydroxyethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one“Peak 2”

Step 1:

To a stirred solution of(rac)-2-bromo-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one(1.0 equiv) in DMF (0.1 M) at 25° C. were added Cs₂CO₃ (12 equiv) and(2-bromoethoxy)-tert-butyldimethylsilane (8 equiv), and the reaction wasstirred at RT for 24 h. The mixture was poured onto water and extractedthree times with ethyl acetate. The combined organics were washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (heptane and 0-60% EtOAc gradient) to give(rac)-2-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneas a colorless oil in 55% yield. LCMS (m/z) (M+H)=453.3/455.3, Rt=1.53min.

Step 2:

To a stirred solution of(rac)-2-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one(1.0 equiv) in DCM (0.1 M) at 25° C. was added TfOH (1.5 equiv) and thereaction was stirred for 30 min. The mixture was partitioned between DCMand saturated aqueous NaHCO₃ and extracted three times with DCM. Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (DCM and 0-20% MeOH gradient) to give(rac)-2-bromo-5-(2-hydroxyethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-oneas a white foam in 96% yield. LCMS (m/z) (M+H)=339.2/341.2, Rt=0.75 min.

Step 3:

(rac)-2-bromo-5-(2-hydroxyethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-onewas subjected chiral SFC (Lux Cellulose-4 21×250 mm column, 45% i-PrOHin CO₂ eluent). The first eluting peak afforded2-bromo-5-(2-hydroxyethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one“Peak 1” as a white foam in 40% yield. The second peak afforded2-bromo-5-(2-hydroxyethyl)-6a,6b,7,9,9a,9b-hexahydrofuro[3′,4′:3,4]cyclobuta[1,2-c][1,8]naphthyridin-6(5H)-one“Peak 2” as a white foam in 43% yield. LCMS data for each enantiomerwere identical. LCMS (m/z) (M+H)=339.2/341.2, Rt=0.75 min.

Synthesis of10-bromo-7-(2-hydroxyethyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“from Peak 4”

Step 1:

To a stirred solution of ethyl5-(5-bromo-2-fluoropyridin-3-yl)oxepane-4-carboxylate (1.0 equiv) in NMP(0.2 M) were added i-Pr₂NEt (5 equiv) followed by 4-methoxybenzylamine(4.5 equiv) were added and the mixture was heated at 150° C. for 48 h.The reaction was poured onto half-saturated NH₄Cl, and extracted twicewith EtOAc The combined organics were washed with water and with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash column chromatography over silica gel (heptane and 0-50% EtOAcgradient) to give10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-oneas a diastereomeric mixture in 69% yield. LCMS (m/z) (M+H)=417.1/419.1,Rt=1.23 and 1.24 min.

Step 2:

10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-onewas subjected chiral SFC (IC 30×250 mm column, 45% i-PrOH in CO₂eluent). The first eluting peak afforded10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 1” as a white foam in 29% yield. The second peak afforded10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 2” as a white foam in 29% yield. These two products were oppositeenantiomers of the same diastereomer; LCMS data for each enantiomer wereidentical. LCMS (m/z) (M+H)=417.0/419.0, Rt=1.23 min. The third elutingpeak afforded10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 3” as a white foam in 13% yield. The fourth peak afforded10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 4” as a white foam in 13% yield. These two products were oppositeenantiomers of the same diastereomer; LCMS data for each enantiomer wereidentical. LCMS (m/z) (M+H)=417.0/419.0, Rt=1.24 min.

Step 3:

To a stirred solution of10-bromo-7-(4-methoxybenzyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“Peak 4” (1.0 equiv) in DCM (0.15 M) was slowly added triflic acid (5equiv) and the mixture was stirred at 25° C. for 1 h. The mixture wasquenched slowly with saturated aqueous Na₂CO₃ and extracted three timeswith DCM. The combined organics were washed with brine, dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash column chromatography over silica gel (DCM and 0-100% EtOAcgradient) to give10-bromo-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“from Peak 4” as a crystalline white solid in 89% yield. LCMS (m/z)(M+H)=297.1/299.1, Rt=0.76.

Step 4:

To a stirred solution of10-bromo-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“from Peak 4” (1.0 equiv) in DMF (0.1 M) at 25° C. were added Cs₂CO₃ (6equiv), (2-bromoethoxy)-tert-butyldimethylsilane (2.8 equiv), and thereaction was stirred for 3 h. The mixture was poured onto water andextracted three times with ethyl acetate. The combined organics werewashed with water and brine, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (heptane and 0-50% EtOAc gradient) to provide10-bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“from Peak 4” as a colorless oil in 88% yield. LCMS (m/z)(M+H)=455.2/457.2, Rt=1.61 min.

Step 5:

To a stirred solution of10-bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“from Peak 4” (1.0 equiv) in DCM (0.1 M) at 25° C. was added TfOH (1.5equiv) and the reaction was stirred for 1 h. The mixture was partitionedbetween DCM and saturated aqueous NaHCO₃ and extracted three times withDCM. The combined organics were dried over magnesium sulfate, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togive10-bromo-7-(2-hydroxyethyl)-1,4,5,5a,7,11b-hexahydrooxepino[4,5-c][1,8]naphthyridin-6(2H)-one“from Peak 4” as a colorless oil in 91% yield. LCMS (m/z)(M+H)=340.9/342.9, Rt=0.79 min.

Example 19-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate

Step 1:

Into a 250 mL RB flask were charged morpholin-3-one (1.0 equiv.) and DCM(0.5 M). To the mixture at room temperature under nitrogen was addedtriethyloxonium tetrafluoroborate (1.0 M in DCM) (13.81 ml, 13.81 mmol)dropwise. The mixture was agitated at room temperature overnight and thenext morning, the reaction mixture was quenched by addition of Sat'dNaHCO₃. The organic layer was separated and dried (MgSO₄), filtered andconcentrated in vacuo (30° C., 250 mmHg) to afford the crude0020product5-ethoxy-3,6-dihydro-2H-1,4-oxazine in quantitative. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 4.12 (q, J=7.13 Hz, 2H) 4.05 (t, J=1.41 Hz, 2H)3.64-3.71 (m, 2H) 3.52-3.60 (m, 2H) 1.29 (t, J=7.09 Hz, 3H).

Step 2:

To the crude product 5-ethoxy-3,6-dihydro-2H-1,4-oxazine from above wasadded ethyl 3-(4-bromophenyl)-3-oxopropanoate (0.8 equiv.). The entiremixture was heated at 115° C. in a Teflon capped vessel for 8 hour uponwhich LCMS indicated formation of desired product. The reaction mixturewas cooled to room temperature and let to stand over the weekend. Thesolid obtained was dissolved in DCM and purified by flash chromatography(0-10% MeOH/DCM) to afford the desired product ethyl9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate.LCMS: (m/z) (M+H)=353.8, Rt=1.03 min.

Step 3:

Into a MW vial were charged ethyl9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate,N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.) and dioxane: DMF(5:1), 0.2 M and then 2M Na₂CO₃ (2.0 equiv). The entire mixture washeated in MW at 120° C. for 15 min, after which LCMS indicated formationof desired product. The reaction mixture was extracted with EtOAc andwashed with water twice and dried (MgSO₄), filtered and concentrated invacuo and the residue purified by reverse-phase HPLC to afford thedesired product ethyl9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylatein 9% isolated yield. LCMS: (m/z) (M+H)=552.3, Rt=1.39 min. 1H NMR (400MHz, DMSO-d6) d ppm 10.73 (s, 1H) 9.00 (d, J=5.01 Hz, 1H) 8.38 (s, 1H)8.29 (d, J=8.19 Hz, 1H) 8.20 (d, J=5.14 Hz, 1H) 7.72-7.80 (m, 3H)7.34-7.56 (m, 2H) 4.87 (s, 2H) 4.10-4.34 (m, 6H) 2.26 (s, 3H) 1.29 (t,J=7.15 Hz, 3H).

Example 29-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicAcid

Step 1:

Into a vial was charged ethyl9-(2-methyl-5-(2(trifluoromethyl)isonicotinamido)phenyl)-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) and then THF:MeOH:Water (3:2:1) (0.2 M) was added and thenLiOH.H2O (5.0 equiv was added. The mixture was agitated at 60° C. for 30min, LCMS indicated formation of desired product as the major species.The reaction mixture was concentrated in vacuo and the residue dissolvedin water (5 mL) and acidified to pH=1 using 4N HCl (in water). Theproduct was extracted with EtOAc. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo to give a pale orange solid, whichwas dissolved in DMSO and purified by reverse-phase HPLC (basic method)to provide the desired product in 6.8% isolated yield. LCMS: (m/z)(M+H)=524.3, Rt=0.81 min (basic method). 1H NMR (400 MHz, DMSO-d6) δ ppm10.76 (s, 1H) 9.00 (d, J=5.01 Hz, 1H) 8.51 (d, J=8.31 Hz, 1H) 8.37 (s,1H) 8.20 (d, J=4.89 Hz, 1H) 8.00 (s, 1H) 7.76-7.84 (m, 2H) 7.72 (dd,J=8.31, 1.10 Hz, 1H) 7.42 (d, J=8.31 Hz, 1H) 5.43 (s, 2H) 4.45 (t,J=5.20 Hz, 2H) 4.15 (t, J=5.26 Hz, 2H) 2.28 (s, 3H).

Example 3(rac)-(trans)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

Into a 30 mL vial was charged ethyl9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) and then THF, MeOH and Water in (3:2:1 ratio, 0.2 M)followed by and LiOH.H₂O (5.0 equiv.) were added. The mixture was heatedat 60° C. for 10 min upon which thick light yellow precipitate developedand it became difficult to stir. At this stage, water was added and thenthe slurry was heated for another 30 min to afford the completehydrolysis of the ethyl ester. The reaction mixture was concentrated invacuo and the residue acidified to pH=1 using 4.0 N HCl (aq). Theprecipitate was collected by filtrated and azeotroped twice with THF andonce with toluene and dried under high vacuum until constant mass toafford the desired product9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid in 77% isolated yield. LCMS: (m/z) (M+H)=325.8, Rt=1.12 min.

Step 2:

9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (1.0 equiv.) was suspended in MeOH (0.15 M) and then NaBH₄ (4.0equiv.) was added in small portions at room temperature in order to keepthe effervescence in control. After completion of NaBH₄ addition,pTsOH.H₂O (0.1 equiv.) was added. The mixture was placed in an oil bathmaintained at 70° C. and agitated for 1 h upon which LCMS indicatedcomplete conversion to the desired product. The reaction mixture wascooled to room temperature and quenched by addition of acetone and thenconcentrated in vacuo. Sat'd NH₄Cl was added to the residue and theproduct was extracted with EtOAc and the organic layer was dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified byflash chromatography (0-50% EtOAc/heptane) to afford the desired product9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-one in40.7% isolated yield as a faint yellow solid. LCMS: (m/z) (M+H)=283.8,Rt=1.29 min.

Step 3:

9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-one (1.0equiv.) was suspended in MeOH (0.3 M) and cooled to The mixture wascooled to 0° C. and then sodium borohydride (2.0 equiv.) was added inportions and the mixture let to warm to room temperature and agitate for2 h upon which LCMS indicated complete ketone reduction. The reactionmixture was quenched by addition of acetone and then the volatilesevaporated in vacuo. The residue was diluted with Sat'd NH₄Cl andextracted with EtOAc and the organic layer dried (MgSO₄), filtered andconcentrated in vacuo to afford an off white solid, which was purifiedby flash chromatography (0-100% EtOAc/heptane) to afford the desiredproduct(trans)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-olas an off white solid in 99% isolated yield. LCMS: (m/z)(M+H−H₂O)=267.9, Rt=1.16 min. The relative stereochemistry of theproduct was confirmed by 2D-NMR and the relative stereochemistry wasestablished to be trans. ¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 7.22 (dd,J=8.19, 0.94 Hz, 1H) 6.86 (dd, J=8.14, 1.83 Hz, 1H) 6.80 (d, J=1.69 Hz,1H) 4.78 (td, J=9.06, 6.45 Hz, 1H) 3.91-3.97 (m, 1H) 3.77 (ddd, J=11.20,3.20, 0.85 Hz, 1H) 3.62 (td, J=11.72, 2.82 Hz, 1H) 3.44 (dd, J=12.33,1.69 Hz, 1H) 3.28 (t, J=10.82 Hz, 1H) 3.17 (tt, J=10.76, 3.02 Hz, 1H)2.79 (td, J=12.09, 3.58 Hz, 1H) 2.07 (ddd, J=12.42, 6.12, 2.92 Hz, 1H)1.70 (d, J=8.47 Hz, 1H) 1.59 (dt, J=12.38, 10.75 Hz, 1H).

Step 4:

Into a MW vial were charged(trans)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.) and then Dioxane(0.13 M) and finally 2M Na₂CO₃ (2.5 equiv.). The mixture was agitated inMW at 120° C. for 15 min and cooled to room temperature. The product wasextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo and the residue purified by reverse-phase HPLC toafford the desired productN-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a free-base in 30.5% isolated yield. LCMS: (m/z) (M+H−H₂O)=466.2,Rt=1.30 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1H) 8.98 (d,J=4.89 Hz, 1H) 8.35 (s, 1H) 8.19 (d, J=5.01 Hz, 1H) 7.68 (dd, J=8.25,2.26 Hz, 1H) 7.60 (d, J=2.32 Hz, 1H) 7.38-7.45 (m, 1H) 7.28 (d, J=8.44Hz, 1H) 6.64-6.74 (m, 2H) 5.36 (d, J=6.85 Hz, 1H) 4.72-4.88 (m, 1H)3.68-3.97 (m, 3H) 3.55 (td, J=11.62, 2.57 Hz, 1H) 3.08-3.27 (m, 2H)2.62-2.79 (m, 1H) 2.22 (s, 3H) 1.90-2.04 (m, 1H) 1.43-1.61 (m, 1H).

Examples 4 and 5(trans)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Racemic(trans)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak affordedN-(3-((4aR,6R)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1H) 8.98 (d, J=5.01 Hz, 1H)8.36 (s, 1H) 8.19 (dd, J=5.01, 1.10 Hz, 1H) 7.68 (dd, J=8.25, 2.26 Hz,1H) 7.60 (d, J=2.32 Hz, 1H) 7.39-7.45 (m, 1H) 7.28 (d, J=8.44 Hz, 1H)6.64-6.73 (m, 2H) 5.36 (d, J=6.72 Hz, 1H) 4.68-4.83 (m, 1H) 3.67-3.97(m, 3H) 3.55 (td, J=11.52, 2.38 Hz, 1H) 3.09-3.26 (m, 2H) 2.61-2.75 (m,1H) 2.22 (s, 3H) 1.94-2.03 (m, 1H) 1.54 (q, J=11.37 Hz, 1H); (m/z)(M+H−H₂O)=466.2, Rt=1.30 min and the second eluting peak affordedN-(3-((4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H) 8.98 (d, J=5.01 Hz, 1H)8.36 (s, 1H) 8.19 (d, J=4.89 Hz, 1H) 7.68 (dd, J=8.19, 2.20 Hz, 1H) 7.60(d, J=2.20 Hz, 1H) 7.39-7.46 (m, 1H) 7.28 (d, J=8.44 Hz, 1H) 6.65-6.75(m, 2H) 5.36 (d, J=6.72 Hz, 1H) 4.71-4.84 (m, 1H) 3.66-3.99 (m, 3H) 3.55(td, J=11.52, 2.38 Hz, 1H) 3.08-3.26 (m, 2H) 2.63-2.76 (m, 1H) 2.22 (s,3H) 1.90-2.05 (m, 1H) 1.54 (q, J=11.41 Hz, 1H); (m/z) (M+H−H₂O)=466.2,Rt=1.30.

The following compounds were made following step 4 of Example 3.

Ex. No. Structure Name Physical Data 6

(rac)-2-(1,1- difluoroethyl)- N-(3-(6-hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methyl- phenyl)isonicotin- amide¹H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.75-9.14 (m, 1 H) 8.17(s, 1 H) 8.02 (dd, J = 5.01, 1.35 Hz, 1 H) 7.68 (dd, J = 8.25, 2.26 Hz,1H) 7.61 (d, J = 2.20 Hz, 1 H) 7.42 (dd, J = 7.76, 0.79 Hz, 1 H) 7.27(d, J = 8.44 Hz, 1 H) 6.64- 6.76 (m, 2 H) 5.36 (d, J = 6.85 Hz, 1 H)4.73-4.87 (m, 1H) 3.68-3.99 (m, 3 H) 3.55 (td, J = 11.62, 2.57 Hz, 1 H)3.08-3.25 (m, 2 H) 2.62- 2.71 (m, 1 H) 2.22 (s, 3 H) 2.05 (t, J = 19.13Hz, 4 H) 1.45-1.62 (m, 1 H); LCMS (m/z) (M + H − H₂O) = 552.1, Rt = 1.26min. 7

(rac)-2-(2- fluoropropan-2- yl)-N-(3-(6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methyl-phenyl)isonicotin- amide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s, 1 H)8.75 (d, J = 5.01 Hz, 1 H) 8.01 (s, 1 H)7.81 (dd, J = 5.01, 1.59 Hz, 1H) 7.68 (dd, J = 8.25, 2.26 Hz, 1 H) 7.60 (d, J = 2.20 Hz, 1 H)7.36-7.45 (m, 1 H) 7.26 (d, J = 8.44 Hz, 1 H) 6.64- 6.76 (m, 2 H) 5.36(d, J = 6.72 Hz, 1 H) 4.70-4.89 (m, 1 H) 3.68-3.94 (m, 3 H) 3.55 (td, J= 11.58, 2.51 Hz, 1 H) 3.08-3.26 (m, 2 H) 2.67 (td, J = 12.01, 3.48 Hz,1 H) 2.22 (s, 3 H) 1.92-2.05 (m, 1 H) 1.62- 1.77 (m, 6 H) 1.43-1.59 (m,1 H); LCMS (m/z) (M + H − H₂O) = 458.3, Rt = 1.28 min. 8

(rac)-2-(2- cyanopropan-2- yl)-N-(3-(6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methyl-phenyl)isonicotin- amide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1 H)8.80 (dd, J = 5.01, 0.73 Hz, 1 H) 7.99 (s, 1 H) 7.85 (dd, J = 5.01, 1.47Hz, 1 H) 7.66 (dd, J = 8.25, 2.26 Hz, 1 H) 7.59 (d, J = 2.20 Hz, 1 H)7.42 (dd, J = 7.76, 0.67 Hz, 1 H) 7.27 (d, J = 8.44 Hz, 1 H) 6.65-6.73(m, 2 H) 5.36 (d, J = 6.72 Hz, 1 H) 4.69- 4.87 (m, 1 H) 3.67-3.96 (m, 3H) 3.55 (td, J = 11.62, 2.57 Hz, 1 H) 3.06-3.27 (m, 2 H) 2.67 (td, J =11.98, 3.42 Hz, 1 H) 2.22 (s, 3 H) 1.94-2.04 (m, 1 H) 1.76 (s, 6 H)1.42-1.61 (m, 1 H); LCMS (m/z) (M + H − H₂O) = 465.3, Rt = 1.22 min. 9

(rac)-N-(5-(6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9-yl)- 6-methylpyridin- 3-yl)-3-(trifluoro- methyl)benz-amide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H) 8.82 (d, J = 2.45Hz, 1 H) 8.21-8.38 (m, 2 H) 7.93- 8.07 (m, 2 H) 7.81 (t, J = 7.83 Hz, 1H) 7.45 (dd, J = 7.76, 0.79 Hz, 1 H) 6.71-6.81 (m, 2 H) 5.39 (d, J =6.85 Hz, 1 H) 4.65-4.89 (m, 1 H) 3.70-3.99 (m, 3 H) 3.56 (td, J = 11.65,2.51 Hz, 1 H) 3.09-3.27 (m, 2 H) 2.62-2.78 (m, 1 H) 2.42 (s, 3 H)1.93-2.05 (m, 1 H) 1.46-1.60 (m, 1 H); LCMS (m/z) (M + H) = 484.2, Rt =1.20 min. 10

(rac)-N-(3-(6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9-yl)- 4-methylphenyl)- 6-(trifluorometh- yl)pyridazine-4-carboxamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H) 9.91 (d, J =1.96 Hz, 1 H) 8.67 (d, J = 2.08 Hz, 1 H) 7.67 (dd, J = 8.19, 2.20 Hz, 1H) 7.60 (d, J = 2.20 Hz, 1 H) 7.40-7.46 (m, 1 H) 7.31 (d, J = 8.44 Hz, 1H) 6.65-6.74 (m, 2 H) 5.37 (d, J = 6.85 Hz, 1 H) 4.71-4.89 (m, 1 H)3.67-4.00 (m, 3H) 3.55 (td, J = 11.58, 2.51 Hz, 1 H) 3.07-3.26 (m, 2 H)2.62-2.77 (m, 1 H) 2.23 (s, 3 H) 1.92-2.04 (m, 1 H) 1.40-1.60 (m, 1 H);LCMS (m/z) (M + H − H₂O) = 467.3, Rt = 1.24 min. 11

(rac)-2-(1,1- difluoroethyl)-N- (5-(6-hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)- 6-methylpyridin- 3-yl)isonicotin-amide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1 H) 8.90 (d, J = 5.01Hz, 1 H) 8.82 (d, J = 2.45 Hz, 1 H) 8.26-8.27 (m, 1 H) 8.20 (s, 1 H)7.92-8.10 (m, 1 H) 7.83-8.07 (m, 1 H) 7.41-7.52 (m, 1 H) 7.38-7.53 (m, 1H) 6.80-6.81 (m, 1 H) 6.64-6.81 (m, 1 H) 5.30-5.48 (m, 1 H) 4.53- 4.96(m, 1 H) 3.71-4.17 (m, 4 H) 3.46-3.64 (m, 1 H) 3.04-3.26 (m, 3 H)2.66-2.75 (m, 1 H) 2.43 (s, 3 H) 2.06 (t, J = 19.13 Hz, 4 H); LCMS (m/z)(M + H) = 481.2, Rt = 0.94 min. 12

(rac)-2-(2- cyanopropan-2- yl)-N-(5-(6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 6-methylpyridin-3-yl)isonicotin- amide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1 H)8.63-9.04 (m, 2 H) 8.00 (dd, J = 17.61, 1.59 Hz, 2 H) 7.88 (dd, J =5.07, 1.53 Hz, 1 H) 7.45(dd, J = 7.83, 0.86 Hz, 1 H) 6.66-6.81 (m, 2 H)5.40 (br s, 1 H) 4.78 (br dd, J = 10.33, 6.17 Hz, 1 H) 3.71-3.98 (m, 3H) 3.56 (td, J = 11.65, 2.63 Hz, 1 H) 3.10-3.26 (m, 2 H) 2.68 (td, J =12.07, 3.48 Hz, 1 H) 2.43 (s, 3 H) 1.95-2.06 (m, 1 H) 1.77 (s, 6 H)1.44-1.64 (m, 1 H); LCMS (m/z) (M + H) = 484.2, Rt = 0.92 min.

Examples 13 and 14(trans)-2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

(trans)-2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,6R)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1H) 8.79-8.95 (m, 1H) 8.17 (s,1H) 8.02 (dd, J=5.01, 1.34 Hz, 1H) 7.54-7.73 (m, 2H) 7.42 (dd, J=7.76,0.67 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 6.54-6.74 (m, 2H) 5.36 (br. s., 1H)4.77 (dd, J=10.64, 6.24 Hz, 1H) 3.69-3.98 (m, 3H) 3.55 (td, J=11.62,2.57 Hz, 1H) 3.05-3.25 (m, 2H) 2.67 (td, J=12.01, 3.48 Hz, 1H) 2.22 (s,3H) 1.89-2.13 (m, 4H) 1.54 (q, J=11.37 Hz, 1H); LCMS (m/z)(M+H−H₂O)=462.1, Rt=1.38 min and the second eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1H) 8.79-8.95 (m, 1H) 8.17 (s,1H) 8.02 (dd, J=5.01, 1.34 Hz, 1H) 7.54-7.73 (m, 2H) 7.42 (dd, J=7.76,0.67 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 6.54-6.74 (m, 2H) 5.36 (br. s., 1H)4.77 (dd, J=10.64, 6.24 Hz, 1H) 3.69-3.98 (m, 3H) 3.55 (td, J=11.62,2.57 Hz, 1H) 3.05-3.25 (m, 2H) 2.67 (td, J=12.01, 3.48 Hz, 1H) 2.22 (s,3H) 1.89-2.13 (m, 4H) 1.54 (q, J=11.37 Hz, 1H); LCMS (m/z)(M+H−H₂O)=462.1, Rt=1.38 min.

(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol

Step 1:

(trans)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.), Triphenylphosphine (1.2 equiv.), Benzoic acid (2.0 equiv.)were suspended in THF (0.25 M) and cooled to 0° C. Then DIAD (1.0equiv.) was added dropwise. The mixture was let to warm to roomtemperature over 2 h upon which LCMS indicated formation of desiredproduct. The reaction mixture was concentrated in vacuo and the residuepurified by flash chromatography (0-30% EtOAc/heptane) to afford thedesired product(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ylbenzoate in quantitative yield. LCMS: (m/z) (M+H)=390.1, Rt=1.71 min.

Step 2:

Into a 30 mL vial was charged(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ylbenzoate and THF, MeOH, Water (3:2:1 ratio, 0.2M) and then at roomtemperature LiOH.H₂O (258 mg, 6.16 mmol) was added. The mixture wasagitated at 70° C. for 30 min and then product extracted with EtOAc. Theorganic layer was washed with Sat'd Na₂CO₃ and dried (MgSO₄), filteredand concentrated in vacuo to afford the desired product(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol asa colorless solid. LCMS: (m/z) (M+H−H₂O)=267.9, Rt=1.16 min.

Example 15(rac)-(cis)-2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Into a MW vial was added(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.),2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide(1.0 equiv), K₃PO₄ (2.0 equiv.), X-Phos G2 Pd-Cy (0.1 equiv.) and thendioxane: water (10:1) (0.2 M). The mixture was heated in MW at 120° C.for 30 min and then cooled to room temperature and the product extractedwith EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo and the residue purified by flash chromatography(0-100% EtOAc/heptane) to afford the desired product as an off whitesolid which was dissolved in 50/50 ACN/water and lyophilized. LCMS (m/z)(M+H−H₂O)=466.3.1, Rt=1.31 min; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.63(s, 1H) 8.98 (d, J=5.01 Hz, 1H) 8.35 (s, 1H) 8.19 (dd, J=4.95, 1.04 Hz,1H) 7.58-7.72 (m, 2H) 7.15-7.49 (m, 2H) 6.79 (d, J=1.10 Hz, 1H)6.63-6.73 (m, 1H) 5.10-5.44 (m, 1H) 4.43-4.88 (m, 1H) 3.48-4.06 (m, 4H)3.01-3.29 (m, 2H) 2.73 (td, J=11.95, 3.48 Hz, 1H) 2.23 (s, 3H) 1.75 (dt,J=13.27, 2.48 Hz, 1H) 1.39-1.61 (m, 1H).

The following compounds were made following Example 15.

Ex. No. Structure Name Physical Data 16

(rac)-2-(1,1- difluoroethyl)-N- (3-(6-hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)- 4- methylphenyl)iso- nicotinamide ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.59 (s, 1 H) 8.87 (dd, J = 5.01, 0.61 Hz,1 H) 8.17 (d, J = 0.61 Hz, 1 H) 8.02 (d, J = 5.01 Hz, 1 H) 7.58-7.73 (m,2 H) 7.18-7.45 (m, 2 H) 6.79 (d, J = 1.10 Hz, 1 H) 6.63-6.74 (m, 1 H)5.13-5.45 (m, 1 H) 4.52-4.89 (m, 1 H) 3.86-4.00 (m, 1 H) 3.69-3.84 (m, 2H) 3.49-3.65 (m, 1 H) 3.10-3.29 (m, 2 H) 2.73 (td, J = 11.95, 3.48 Hz, 1H) 2.22 (s, 3 H) 1.93- 2.11 (m, 3 H) 1.75 (dt, J = 13.27, 2.48 Hz, 1H)1.42-1.61 (m, 1 H); LCMS (m/z) (M + H − H₂O) = 462.4, Rt = 1.30 min. 17

(rac)-2-(2- fluoropropan-2- yl)-N-(3-(6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4- methylphenyl)iso-nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (s, 1 H) 8.75 (d, J =5.13 Hz, 1 H) 8.01 (s, 1 H) 7.81 (dd, J = 5.01, 1.59 Hz, 1 H) 7.67 (dd,J = 8.25, 2.26 Hz, 1 H) 7.55-7.64 (m, 1 H) 7.17-7.46 (m, 2 H) 6.79 (d, J= 1.10 Hz, 1 H) 6.63-6.73 (m, 1 H) 5.36 (d, J = 6.72 Hz, 1 H) 5.18 (d, J= 5.01 Hz, 8 H)4.72-4.83 (m, 1 H) 4.51-4.62 (m, 8 H) 3.87-4.03 (m, 1 H)3.66-3.85 (m, 2 H) 3.59 (td, J = 11.68, 2.57 Hz, 1 H) 3.06-3.29 (m, 2 H)2.64- 2.82 (m, 1 H) 2.22 (s, 3 H) 1.64-1.78 (m, 7 H) 1.43-1.60 (m, 1 H);LCMS (m/z) (M + H − H₂O) = 458.4, Rt = 1.29 min. 18

(rac)-N-(5-(6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9-yl)- 6-methylpyridin- 3-yl)-3-(trifluoro- methyl)benzamide¹H NMR (400 MHz, DMSO-d6) δ ppm 10.50-10.87 (m, 1 H) 8.75-9.07 (m, 1 H)8.24-8.47 (m, 2 H) 7.91-8.12 (m, 2 H) 7.81 (t, J = 7.83 Hz, 1 H)7.25 (d,J = 7.83 Hz, 1 H) 6.67-6.96 (m, 2 H) 5.13- 5.49 (m, 1 H) 4.54-4.93 (m, 1H) 3.71- 4.05 (m, 3 H) 3.59 (td, J = 11.65, 2.63 Hz, 1 H) 3.11-3.27 (m,2 H) 2.74 (td, J = 12.01, 3.48 Hz, 1 H) 2.42 (s, 3 H) 1.76 (dt, J =13.30, 2.46 Hz, 1 H) 1.44- 1.62 (m, 1 H); LCMS (m/z) (M + H) = 484.3, Rt= 1.22 min.

Examples 19 and 20(cis)-2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

(cis2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.17 (s, 1H) 7.89-8.06 (m, 1H) 7.57-7.76 (m, 2H) 7.15-7.35 (m, 2H) 6.79(d, J=1.10 Hz, 1H) 6.68 (dd, J=7.64, 1.41 Hz, 1H) 5.18 (d, J=4.52 Hz,1H) 4.57 (d, J=2.32 Hz, 1H) 3.94 (dd, J=11.25, 2.93 Hz, 1H) 3.69-3.86(m, 2H) 3.59 (td, J=11.58, 2.63 Hz, 1H) 3.12-3.28 (m, 2H) 2.73 (td,J=11.98, 3.55 Hz, 1H) 2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.75 (dt,J=13.33, 2.38 Hz, 1H) 1.43-1.60 (m, 1H); LCMS (m/z) (M+H−H₂O)=462.4,Rt=1.30 min and the second eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aS,6R)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.17 (s, 1H) 7.89-8.06 (m, 1H) 7.57-7.76 (m, 2H) 7.15-7.35 (m, 2H) 6.79(d, J=1.10 Hz, 1H) 6.68 (dd, J=7.64, 1.41 Hz, 1H) 5.18 (d, J=4.52 Hz,1H) 4.57 (d, J=2.32 Hz, 1H) 3.94 (dd, J=11.25, 2.93 Hz, 1H) 3.69-3.86(m, 2H) 3.59 (td, J=11.58, 2.63 Hz, 1H) 3.12-3.28 (m, 2H) 2.73 (td,J=11.98, 3.55 Hz, 1H) 2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.75 (dt,J=13.33, 2.38 Hz, 1H) 1.43-1.60 (m, 1H); LCMS (m/z) (M+H−H₂O)=462.4,Rt=1.30 min.

Example 21(rac)-N-(3-(1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

Into a MW vial was charged(trans)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.) and then Triethylsilane (8.9 equiv.) followed by TFA (18.4equiv). The mixture was agitated in MW at 140° C. for 15 min duringwhich LCMS indicated formation of desired product. The reaction mixturewas diluted with EtOAc and treated with Sat'd Na₂CO₃ and after theeffervescence subsided, the product was extracted with EtOAc. Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo toafford the crude product9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline which wastaken to the next step as such. LCMS: (m/z) (M+H)=269.8, Rt=1.22 min.

Step 2:

9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline (1.0equivN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.) were combined indioxane (1.5 mL) and then 2 M Na₂CO₃ (2.0 equiv.) was added. The mixturewas heated in MW at 120° C. for 30 min and then cooled to roomtemperature. The mixture was extracted with EtOAc and dried (Na₂SO₄),filtered and concentrated in vacuo and purified by reverse-phase HPLCand the product fractions combined and lyophilized and the obtainedsolid was further purified by prep TLC (50% EtOAc/heptane), and thesilica was scraped and suspended in DCM/MeOH (10:1) and filtered. Thefiltrate was concentrated in vacuo and dissolved in ACN/water (50:50)and frozen and lyophilized to affordN-(3-(1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 4% isolated yield. LCMS (m/z) (M+H−H₂O)=468.1, Rt=1.58 min; ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.50-10.72 (m, 1H) 8.98 (d, J=5.01 Hz, 1H)8.36 (s, 1H) 8.19 (dd, J=4.95, 1.16 Hz, 1H) 7.53-7.70 (m, 2H) 7.28 (d,J=8.31 Hz, 1H) 7.01 (d, J=7.46 Hz, 1H) 6.74 (d, J=1.22 Hz, 1H) 6.62 (dd,J=7.52, 1.41 Hz, 1H) 3.79-3.97 (m, 2H) 3.70 (d, J=11.62 Hz, 1H) 3.56(td, J=11.62, 2.69 Hz, 1H) 3.21 (t, J=10.70 Hz, 1H) 3.00 (tt, J=10.38,3.01 Hz, 1H) 2.80-2.93 (m, 1H) 2.64-2.78 (m, 2H) 2.22 (s, 3H) 1.77-1.98(m, 1H) 1.49-1.67 (m, 1H).

Example 22(rac)-N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-one (1.0equiv.) was dissolved in Tetrahydrofuran (0.1 M) and cooled to 0° C.Then methylmagnesium iodide (1.5 equiv.) was added dropwise upon whichthe mixture turns turbid yellow. After 2 h, reaction appears to besaturated. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(0-100% EtOAc/heptane) to afford the desired product(trans)-9-bromo-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-olin 58% isolated yield. LCMS: (m/z) (M+H−H₂O)=281.9, Rt=1.22 min.

Step 2.

(trans)-9-bromo-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.)), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.) were combined indioxane (0.1 M) and then 2 M Na₂CO₃ (2.0 equiv.) was added. The mixturewas heated in MW at 120° C. for 25 min and then diluted with EtOAc. Theorganic layer was washed with brine and dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(0-100% EtOAc/heptane) to afford the desired productN-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas an off-white solid. LCMS (m/z) (M+H−H₂O)=480.1, Rt=1.41 min; ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.53-10.66 (m, 1H) 8.99 (d, J=5.01 Hz, 1H)8.35 (s, 1H) 8.18 (dd, J=5.01, 1.10 Hz, 1H) 7.60-7.73 (m, 2H) 7.49 (d,J=7.70 Hz, 1H) 7.28 (d, J=8.31 Hz, 1H) 6.58-6.75 (m, 2H) 4.97-5.14 (m,1H) 3.51-4.01 (m, 4H) 2.99-3.26 (m, 2H) 2.64-2.80 (m, 1H) 2.23 (s, 3H)1.69-1.86 (m, 2H) 1.34-1.54 (m, 3H).

The compound of Example 23 was prepared according to the above methodsusing appropriate starting materials:

23

(rac)-2-(1,1- difluoroethyl)- N-(3-(6- hydroxy-6- methyl- 1,2,4,4a,5,6-hexahydro- [1,4]oxaz- ino[4,3- a]quinolin-9- yl)-4-methyl- ¹H NMR (400MHz, DMSO-d6) δ ppm 10.45-10.68 (m, 1 H) 8.76-9.00 (m, 1 H) 8.17 (s, 1H) 8.02 (dd, J = 5.01, 1.47 Hz, 1 H) 7.60-7.70 (m, 2 H) 7.49 (d, J =7.70 Hz, 1 H) 7.27 (d, J = 8.31 Hz, 1 H) 6.64-6.79 (m, 2 H) 5.00-5.11(m, 1 H) 3.50-4.02 (m, 4 H) 3.01-3.25 (m, 2 H) 2.63- 2.83 (m, 1 H) 2.23(s, 3 H) 2.05 (t, J = 19.13 Hz, 4 H) 1.64-1.80 (m, 2 H) 1.35-1.53 (m, 3H); LCMS (m/z) phenyl)iso- (M + H − H₂O) = 476.1, Rt = 1.41 nicotinamidemin.

Examples 24 and 25N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,6R)-6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H) 8.87 (dd, J=5.01, 0.73 Hz,1H) 8.17 (s, 1H) 8.02 (d, J=4.89 Hz, 1H) 7.60-7.71 (m, 2H) 7.49 (d,J=7.70 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 6.65-6.76 (m, 2H) 5.04 (s, 1H)3.70-3.98 (m, 3H) 3.56 (td, J=11.55, 2.57 Hz, 1H) 3.01-3.15 (m, 1H)2.68-2.76 (m, 1H) 2.23 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.69-1.84 (m,2H) 1.43 (s, 3H); LCMS (m/z) (M+H−H₂O)=476.1, Rt=1.41 min; and thesecond eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aS,6S)-6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H) 8.87 (dd, J=5.01, 0.61 Hz,1H) 8.17 (s, 1H) 8.02 (dd, J=5.01, 1.59 Hz, 1H) 7.59-7.72 (m, 2H) 7.49(d, J=7.70 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 6.59-6.82 (m, 2H) 5.04 (br s,1H) 3.70-4.02 (m, 3H) 3.56 (td, J=11.68, 2.57 Hz, 2H) 2.99-3.19 (m, 2H)2.68-2.79 (m, 1H) 2.23 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.66-1.82 (m,2H) 1.43 (s, 3H; LCMS (m/z) (M+H−H₂O)=476.1, Rt=1.41 min.

Examples 26 and 27(rac)-N-(3-(6-hydroxy-4a-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

Ethyl9-bromo-6-oxo-1,2,4,6-tetrahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was charged into a vial and CuI (2.0 equiv) followed by THF(0.1 M) were added. The mixture was cooled under nitrogen to −78° C.during which the reaction mass becomes very difficult to stir. Thenmethylmagnesium bromide (3.0 M in diethyl ether) (4.5 equiv.) was addeddropwise and the mixture agitated vigorously at same temperature for 1 hduring which LCMS indicated formation of desired product (LCMS:MH+=370.0, 1.45 min,) along with unreacted starting material.Accordingly, the reaction mixture was warmed to −40° C. and more MeMgBr(1.5 mL) was added and the mixture agitated for another hour. Finally,the reaction mixture was quenched by addition of citric acid and EtOAc.the biphasic mixture was filtered through celite and the aq. layerextracted with EtOAc. The combined organic layer was dried (MgSO₄),filtered and concentrated in vacuo and the residue purified by flashchromatography (0-30% EtOAc/heptane) to afford the desired product ethyl9-bromo-4a-methyl-6-oxo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylateas a yellow solid in 19% isolated yield. LCMS: (m/z) (M+H)=370.0,Rt=1.45 min).

Step 2:

9-bromo-4a-methyl-6-oxo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate(1.0 equiv.) was suspended in TFA (0.1 M) and heated at 120° C. for 3 hduring which complete decarboxylation was observed. The reaction mixturewas poured over Sat'd K₂CO₃ and the product extracted with EtOAc. Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by flash chromatography to afford the desiredproduct9-bromo-4a-methyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-oneas a faint yellow solid in 54% isolated. LCMS: (m/z) (M+H)=298.0,Rt=1.36 min).

Step 3:

9-bromo-4a-methyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-one(1.0 equiv.) was suspended in MeOH (0.04 M) and then NaBH₄ (3.0 equiv)was added at room temperature. The mixture was agitated for 30 min andquenched by addition of acetone. The volatiles were evaporated in vacuo.The residue was diluted with EtOAc and washed with water and brine anddried (MgSO₄), filtered and concentrated in vacuo. The crude material9-bromo-4a-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-olwas taken to the next step without any further purification. LCMS: (m/z)(M+H)=298.1, Rt=1.23 min).

Step 4:

Into a vial were charged9-bromo-4a-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.) were combined indioxane (0.1 M) and then 2 M Na₂CO₃ (2.0 equiv.) was added. and themixture agitated at 100° C. for 20 min in MW. The reaction mixture wascooled to room temperature and diluted with EtOAc and washed with brine.The organic layer was dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by basic HPLC to afford two separatediastereomers. The first eluting diastereomer was determined to be transby 2D-NMR.(trans)-N-(3-(6-hydroxy-4a-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide.LCMS: (m/z) (M+H)=494.4, Rt=1.33 min; ¹H NMR (400 MHz, DMSO-d6) δ ppm10.56 (s, 1H) 8.87 (dd, J=5.01, 0.61 Hz, 1H) 8.76-9.04 (m, 1H) 8.17 (d,J=0.61 Hz, 1H) 7.93-8.07 (m, 1H) 7.65-7.73 (m, 1H) 7.56-7.63 (m, 1H)7.46 (dd, J=7.70, 0.86 Hz, 1H) 7.27 (d, J=8.56 Hz, 1H) 6.67 (dd, J=7.70,1.47 Hz, 1H) 6.54-6.59 (m, 1H) 6.51 (s, 1H) 5.15-5.40 (m, 1H) 4.77 (dt,J=11.37, 6.72 Hz, 1H) 3.96 (dd, J=11.31, 3.61 Hz, 1H) 3.51-3.65 (m, 2H)3.42 (dd, J=10.03, 2.45 Hz, 1H) 3.24 (d, J=11.25 Hz, 1H) 2.82 (td,J=12.35, 3.91 Hz, 1H) 2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.87 (dd,J=12.17, 6.79 Hz, 1H) 1.50-1.64 (m, 1H) 1.04-1.21 (m, 3H).(cis)-N-(3-(6-hydroxy-4a-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide.LCMS: (m/z) (M+H)=494.4, Rt=1.33 min; ¹H NMR (400 MHz, DMSO-d6) δ ppm10.57 (s, 1H) 8.87 (dd, J=5.01, 0.61 Hz, 1H) 8.18 (d, J=0.61 Hz, 1H)8.03 (dd, J=5.01, 1.47 Hz, 1H) 7.70 (dd, J=8.25, 2.26 Hz, 1H) 7.62 (d,J=2.32 Hz, 1H) 7.18-7.39 (m, 2H) 6.72 (dd, J=7.70, 1.47 Hz, 1H) 6.58 (d,J=1.34 Hz, 1H) 5.23 (d, J=4.65 Hz, 1H) 4.63 (q, J=4.77 Hz, 1H) 3.96 (dd,J=11.13, 3.67 Hz, 1H) 3.48-3.62 (m, 2H) 3.26 (br d, J=2.81 Hz, 1H) 2.96(td, J=12.26, 3.97 Hz, 1H) 2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.84(dd, J=13.63, 5.81 Hz, 1H) 1.69 (dd, J=13.57, 4.52 Hz, 1H) 1.19 (s, 3H).

Example 28(rac)-N-(3-(6-amino-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-one (1.0equiv.) and Racemic-2-methylpropane-2-sulfinamide (1.0 equiv) weresuspended in THF (0.5 M). To the mixture was added tetraethoxytitanium(2.0 equiv.) and the solution was agitated at 60° C. overnight. The nextmorning, LCMS indicated formation of the two requisite diastereomersalong with unreacted starting material (major). Accordingly, addedanother 10 equiv of Titanium tetraethoxide and agitated at 70° C. foradditional 24 h. After the elapsed time, the reaction mixture wasdiluted with EtOAc and brine and made slurry, which was then filteredthrough celite. The filtrate was concentrated in vacuo and the residuewas purified by flash chromatography (0-50% EtOAc/heptane) to afford thedesired productN-(9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-ylidene)-2-methylpropane-2-sulfinamideas a mixture of diastereomers. LCMS: (m/z) (M+H)=387.0, Rt=1.48 andRt=1.52 min.

Step 2:

N-(9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-ylidene)-2-methylpropane-2-sulfinamide(1.0 equiv.) was dissolved in MeOH:THF (1:1) (0.06 M) and then NaBH₄(2.0 equiv.) was added at room temperature and the reaction agitated for1 h upon which LCMS indicated formation of desired product. The reactionmixture was quenched by addition of acetone and concentrated in vacuo.The residue was dissolved in EtOAc and washed with Sat'd NH₄Cl and dried(MgSO₄), filtered and concentrated in vacuo to afford the crude productN-(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-yl)-2-methylpropane-2-sulfinamidein quantitative yield. LCMS: (m/z) (M+H)=388.9, Rt=1.35 and Rt=1.39 min.

Step 3:

N-(9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-ylidene)-2-methylpropane-2-sulfinamide(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) were charged into a microwave vial and then dioxane/DMF(6:1) (0.1 M) were added. Then 2M Na₂CO₃ (3.0 equiv) was added. Themixture was agitated in MW at 120° C. for 25 min upon which LCMSindicated formation of desired product as major species. The reactionmixture was diluted with EtOAc and washed with water and dried (MgSO₄),filtered and concentrated in vacuo to afford the crude productN-(3-(6-((tert-butylsulfinyl)amino)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewhich was taken to the next step as such. LCMS: (m/z) (M+H)=587.2,Rt=1.55 min.

Step 4:

N-(3-(6-((tert-butylsulfinyl)amino)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) was dissolved in of MeOH (0.05 M) and treated with 4.0 NHCl in dioxane (40 equiv.). The mixture was agitated at room temperaturefor 30 min and concentrated in vacuo and the residue was dissolved inMeOH and purified by reverse-phase HPLC to afford the desired productN-(3-(6-amino-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 10% yield as free base; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H)8.99 (d, J=5.01 Hz, 1H) 8.50 (br. s., 2H) 8.36 (s, 1H) 8.20 (dd, J=4.95,1.04 Hz, 1H) 7.63-7.71 (m, 2H) 7.48 (d, J=7.95 Hz, 1H) 7.31 (d, J=8.19Hz, 1H) 6.87 (d, J=1.22 Hz, 1H) 6.81 (dd, J=7.89, 1.28 Hz, 1H) 4.58-4.75(m, 1H) 3.85-4.06 (m, 3H) 3.76 (d, J=11.74 Hz, 1H) 3.59 (td, J=11.68,2.45 Hz, 1H) 3.09-3.26 (m, 2H) 2.63-2.80 (m, 1H) 2.11-2.26 (m, 3H) 1.65(q, J=11.53 Hz, 1H); LCMS: (m/z) (M−H)—==481.4, Rt=1.28 min (basicmethod).

Example 29(rac)-N-(3-(6-acetamido-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)

Step 1:

N-(3-(6-amino-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas dissolved in Pyridine (0.05 M) and treated with Acetic anhydride (40equiv). The mixture was agitated at room temperature for 30 min uponwhich LCMS indicated formation of desired product. RM was dissolved inEtOAc and washed with Sat'd NH₄Cl and then dried (MgSO₄), filtered andconcentrated in vacuo. The residue was dissolved in DMSO and purified byreverse-phase HPLC to afford the desired productN-(3-(6-acetamido-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas free-base in 16% isolated yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm10.63 (s, 1H) 8.99 (d, J=5.01 Hz, 1H) 8.35 (s, 1H) 8.25 (d, J=8.93 Hz,1H) 8.18 (dd, J=5.01, 1.10 Hz, 1H) 7.67 (dd, J=8.25, 2.26 Hz, 1H) 7.61(d, J=2.20 Hz, 1H) 7.29 (d, J=8.44 Hz, 1H) 7.09 (dd, J=7.76, 0.92 Hz,1H) 6.77 (d, J=1.22 Hz, 1H) 6.70 (dd, J=7.76, 1.41 Hz, 1H) 5.15 (ddd,J=11.62, 8.50, 6.54 Hz, 1H) 3.68-3.98 (m, 3H) 3.57 (td, J=11.62, 2.45Hz, 1H) 3.08-3.24 (m, 2H) 2.62-2.74 (m, 1H) 2.15-2.25 (m, 3H) 1.86-1.99(m, 4H) 1.47-1.60 (m, 1H); LCMS: (m/z) (M+H)=525.4, Rt=1.36 min.

Example 30(rac)-(trans)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

trans-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol(1.0 equiv.) was dissolved in DMF (0.3M) and cooled to 0° C. Then NaH(1.2 equiv.) was added in one portion after which the reaction becamepale yellow in color. The mixture was agitated for 10 min and theniodomethane (2.0 M in MTBE) (1.5 equiv.) was added dropwise and themixture let to warm to room temperature. The mixture was agitated for 2h and then quenched by addition of water. The product was extracted withEtOAc. The organic layer was dried (MgSO₄), filtered and concentrated invacuo. The residue9-bromo-6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolinewas taken to the next step without any further purification. LCMS: (m/z)(M+H)=298.0, Rt=1.46 min.

Step 2:

Into a vial were charged9-bromo-6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) were charged into a microwave vial and then dioxane (0.1 M)was added. Then 2 M Na₂CO₃ was added and the mixture agitated at 120° C.in MW for 30 min and then the mixture was cooled to room temperature anddiluted with brine and EtOAc and filtered through celite. The organiclayer was separated and passed through a plug of Na₂SO₄ and the filtrateconcentrated in vacuo. The residue was dissolved in DMSO and purified byreverse-phase HPLC to afford the desired productN-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas free base in 34% isolated yield. LCMS: (m/z) (M+H)=496.5, Rt=1.51min. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) ä ppm10.63 (s, 1H) 8.99 (d, J=4.89 Hz, 1H) 8.36 (s, 1H) 8.19 (d, J=4.89 Hz,1H) 8.03 (s, 1H) 7.54-7.74 (m, 2H) 7.23-7.37 (m, 1H) 6.61-6.79 (m, 1H)4.59 (dd, J=10.15, 5.99 Hz, 1H) 3.79-3.98 (m, 2H) 3.72 (br d, J=11.74Hz, 1H) 3.56 (td, J=11.62, 2.57 Hz, 1H) 3.39 (s, 3H) 3.07-3.30 (m, 2H)2.68 (td, J=12.07, 3.48 Hz, 1H) 2.15-2.30 (m, 4H) 1.48 (q, J=11.09 Hz,1H).

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

Ex. No. Structure Name Physical Data 31

(rac)-(trans)-2-(1,1- difluoroethyl)-N- (5-(6-methoxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (s, 1 H)8.79-9.03 (m, 2 H) 8.21 (d, J = 0.61 Hz, 1 H) 7.98-8.09 (m, 2 H) 7.36(dd, J = 7.76, 0.79 Hz, 1H) 6.63-6.88 (m, 2 H) 4.59 (dd, J = 9.96, 6.05Hz, 1 H) 3.71-4.04 (m, 3 H) 3.52- 3.63 (m, 2 H) 3.27 (d, J = 10.64 Hz, 2H) 3.11-3.22 (m, 2 H) 2.67-2.78 (m, 1 H) 2.44 (s, 3 H) 2.27 (ddd, J =12.23, 5.99, 2.32 Hz, 1 H) 2.06 (t, J = 19.13 Hz, 3 H) 1.40-1.60 (m, 1H); LCMS (m/z) (M + H − H₂O) = 495.5, Rt = 1.27 min. 32

(rac)-(trans)-N-(5- (6-methoxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-3-(trifluoro-methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.20-10.92 (m, 1 H)8.78- 8.98 (m, 1 H) 8.23-8.41 (m, 2 H) 7.94-8.10 (m, 2 H) 7.81 (t, J =7.82 Hz, 1 H) 7.36 (dd, J = 7.76, 0.79 Hz, 1 H) 6.64-6.84 (m, 2 H) 4.59(dd, J = 10.21, 6.05 Hz, 1 H) 3.72-4.00 (m, 3 H) 3.56 (td, J = 11.65,2.63 Hz, 1 H) 3.40 (s, 3 H) 3.24-3.29 (m, 1 H) 3.11-3.21 (m, 1 H)2.64-2.82 (m, 1 H) 2.42 (s, 3 H) 2.19-2.30 (m, 1 H) 1.36-1.59 (m, 1 H);LCMS (m/z) (M + H − H₂O) = 498.0, Rt = 1.40 min.

Example 33(trans)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

(trans)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(1.0 equiv.) was dissolved in DMF (0.1M) and cooled to 0° C. Then NaH(1.2 equiv.) was added in one portion after which the reaction becamepale yellow in color. The mixture was agitated for 10 min and theniodomethane (2.0 M in MTBE) (1.5 equiv.) was added dropwise and themixture let to warm to room temperature and agitate for 2 h upon whichLCMS indicated formation of desired product. The reaction mixture wasquenched by addition of water and the product extracted with EtOAc. Theorganic layer was washed with water and dried (MgSO₄), filtered andconcentrated in vacuo and the residue9-bromo-6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridinetaken to the next step without any further purification. LCMS: (m/z)(M+H)=298.1, Rt=0.81 min.

Step 2:

Into a vial were charged9-bromo-6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(crude) (1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) were charged into a microwave vial and then dioxane (0.1 M)was added. Then 2 M Na₂CO₃ (2.5 equiv.) was added and the mixtureagitated at 100° C. in a heating block for 1 h upon which completeconversion to desired product was observed. The reaction mixture wascooled to room temperature and diluted with brine and EtOAc and filteredthrough celite. The organic layer was separated and passed through aplug of Na₂SO₄ and the filtrate concentrated in vacuo. The residue wasdissolved in DMSO and purified by reverse-phase HPLC to afford thedesired product2-(1,1-difluoroethyl)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas free base in 49.6% isolated yield. LCMS: (m/z) (M+H)=495.2, Rt=1.25min. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H) 8.88 (dd, J=5.01,0.73 Hz, 1H) 8.18 (d, J=0.73 Hz, 1H) 8.03 (dd, J=5.07, 1.53 Hz, 1H) 7.91(d, J=1.71 Hz, 1H) 7.74 (dd, J=8.31, 2.20 Hz, 1H) 7.65 (d, J=2.20 Hz,1H) 7.33 (d, J=8.44 Hz, 1H) 7.18 (s, 1H) 4.53 (dd, J=9.41, 6.48 Hz, 1H)3.70-3.98 (m, 3H) 3.55 (td, J=11.71, 2.75 Hz, 1H) 3.50 (s, 3H) 3.14-3.27(m, 2H) 2.64-2.83 (m, 2H) 2.16-2.29 (m, 4H) 1.90-2.11 (m, 3H) 1.69 (dt,J=12.93, 9.86 Hz, 1H).

The compound of Example 34 was prepared using methods from the aboveexamples and appropriate starting materials:

34

(rac)-(trans)-N-(3-(6- methoxy-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.68(s, 1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.36 (s, 1 H) 8.19 (dd, J = 5.01,1.10 Hz, 1 H) 7.91 (d, J = 1.71 Hz, 1H) 7.73 (dd, J = 8.31, 2.20 Hz, 1H) 7.65 (d, J = 2.20 Hz, 1 H) 7.34 (d, J = 8.44 Hz, 1 H) 7.17 (d, J =1.71 Hz, 1 H) 4.53 (dd, J = 9.29, 6.48 Hz, 1 H) 3.69-3.97 (m, 3 H) 3.55(td, J = 11.68, 2.69 Hz, 1 H) 3.49 (s, 3 H) 3.14-3.26 (m, 1 H) 2.64-2.84(m, 1 H) 2.13-2.29 (m, 4 H) 1.69 (dt, J = 12.87, 9.83 Hz, 1 H); LCMS(m/z) (M + H) = 499.1, Rt = 1.28 min.

Examples 35 and 362-(1,1-difluoroethyl)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

(trans)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,6R)-6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H) 8.88 (dd, J=5.01, 0.73 Hz,1H) 8.18 (d, J=0.73 Hz, 1H) 8.03 (dd, J=5.07, 1.53 Hz, 1H) 7.91 (d,J=1.71 Hz, 1H) 7.74 (dd, J=8.31, 2.20 Hz, 1H) 7.65 (d, J=2.20 Hz, 1H)7.33 (d, J=8.44 Hz, 1H) 7.18 (s, 1H) 4.53 (dd, J=9.41, 6.48 Hz, 1H)3.70-3.98 (m, 3H) 3.55 (td, J=11.71, 2.75 Hz, 1H) 3.50 (s, 3H) 3.14-3.27(m, 2H) 2.64-2.83 (m, 2H) 2.16-2.29 (m, 4H) 1.90-2.11 (m, 3H) 1.69 (dt,J=12.93, 9.86 Hz, 1H); LCMS: (m/z) (M+H)=495.2, 1.25 min; and the secondeluting peak2-(1,1-difluoroethyl)-N-(3-((4aS,6S)-6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H) 8.88 (dd, J=5.01, 0.73 Hz,1H) 8.18 (d, J=0.73 Hz, 1H) 8.03 (dd, J=5.07, 1.53 Hz, 1H) 7.91 (d,J=1.71 Hz, 1H) 7.74 (dd, J=8.31, 2.20 Hz, 1H) 7.65 (d, J=2.20 Hz, 1H)7.33 (d, J=8.44 Hz, 1H) 7.18 (s, 1H) 4.53 (dd, J=9.41, 6.48 Hz, 1H)3.70-3.98 (m, 3H) 3.55 (td, J=11.71, 2.75 Hz, 1H) 3.50 (s, 3H) 3.14-3.27(m, 2H) 2.64-2.83 (m, 2H) 2.16-2.29 (m, 4H) 1.90-2.11 (m, 3H) 1.69 (dt,J=12.93, 9.86 Hz, 1H); LCMS: (m/z) (M+H)=495.2, Rt=1.25 min.

(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-6-ol

Step 1:

(trans)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(1.0 equiv.) Triphenylphosphine (1.2 equiv.), Benzoic acid (2.0 equiv.)were suspended in THF (0.25 M) and cooled to 0° C. Then DIAD (1.0equiv.) was added dropwise and the mixture was let to warm to roomtemperature over 2 h upon which LCMS indicated formation of desiredproduct. The reaction mixture was concentrated in vacuo and the residuepurified by flash chromatography (0-30% EtOAc/heptane) to afford thedesired product(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ylbenzoate in quantitative. LCMS: (m/z) (M+H)=390.1, Rt=1.71 min.

Step 2:

Into a 30 mL vial was charged(cis)-9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ylbenzoate (1.0 equiv.) and THF (0.1) and then at room temperature, 1.0 MLiOH.H2O (5 equiv.) was added. The mixture was agitated at 70° C. for 1h and then product extracted with EtOAc. The organic layer was washedwith Sat'd Na₂CO₃ and dried (MgSO₄), filtered and concentrated in vacuo.The residue9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olwas taken to the next step without any further purification assumingquantitative yield. LCMS: (m/z) (M+H)=285.8, Rt=1.16 min.

Example 37(rac)-(cis)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

Into a vial were charged9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), 2M Na₂CO₃ (2.5 equiv.) and the mixture agitated at 100° C.in a heating block for 1 h upon which complete conversion to desiredproduct was observed. The reaction mixture was cooled to roomtemperature and diluted with brine and EtOAc and filtered throughcelite. The organic layer was separated and passed through a plug ofNa₂SO₄ and the filtrate concentrated in vacuo. The residue was dissolvedin DMSO and purified by reverse-phase HPLC to afford the desired productN-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas free base in 54% isolated yield. LCMS: (m/z) (M+H)=485.1, Rt=1.21min. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H) 10.50-10.97 (m, 1H)8.99 (d, J=5.01 Hz, 1H) 8.36 (s, 1H) 8.19 (dd, J=5.01, 1.10 Hz, 1H) 7.90(d, J=1.59 Hz, 1H) 7.72 (dd, J=8.25, 2.26 Hz, 1H) 7.66 (d, J=2.32 Hz,1H) 7.34 (d, J=8.44 Hz, 1H) 7.25 (d, J=1.47 Hz, 1H) 5.42 (br s, 1H) 4.60(br s, 1H) 3.77-4.08 (m, 3H) 3.58 (td, J=11.65, 2.63 Hz, 1H) 3.10-3.27(m, 2H) 2.75 (td, J=12.01, 3.48 Hz, 1H) 2.24 (s, 3H) 1.80-1.96 (m, 1H)1.53-1.72 (m, 1H).

The compound of Example 38 was prepared using methods from the aboveexamples, using appropriate starting materials:

38

(rac)-(cis)-N-(5-(6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3-(trifluoro-methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s, 1 H) 8.87 (d,J = 2.45 Hz, 1 H) 8.22-8.41 (m, 2 H) 8.05 (d, J = 2.45 Hz, 1 H) 8.00(dd, J = 7.76, 0.67 Hz, 1 H) 7.94 (d, J = 1.71 Hz, 1 H) 7.81 (t, J =7.82 Hz, 1 H) 7.33 (d, J = 1.59 Hz, 1 H) 5.54-5.54 (m, 1 H) 5.45 (d, J =4.40 Hz, 1 H) 4.53-4.73 (m, 1H) 3.78-4.07 (m, 3 H) 3.58 (td, J = 11.68,2.69 Hz, 1H) 3.13-3.27 (m, 2 H) 2.77 (td, J = 12.04, 3.55 Hz, 1 H) 2.44(s, 3 H) 1.86 (br d, J = 13.69 Hz, 1H) 1.57-1.71 (m, 1 H); LCMS (m/z)(M + H) = 485.1, Rt = 1.14 min.

Examples 39 and 40(rac)-N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1.0 equiv.) was dissolved in Tetrahydrofuran (0.1 M) and cooled to 0°C. Then 3.0 M methylmagnesium iodide in ether (2.5 equiv.) was addeddropwise upon which the mixture turns turbid yellow. After 2 h, reactionappears to be saturated. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by flashchromatography (0-100% EtOAc/heptane) to afford the desired product9-bromo-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olas a 2.7:1 diastereomeric mixture in which the trans-adduct was major;in 68.1% isolated yield. LCMS: (m/z) (M+H−H₂O)=301.0, Rt=0.78 min.

Step 2:

Into a vial were charged(trans)-9-bromo-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-((1.0equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) and 2M Na2CO3 (2.5 equiv.) and the mixture agitated at 120°C. in MW for 30 min and then the reaction mixture was cooled to roomtemperature and diluted with brine and EtOAc and filtered throughcelite. The organic layer was separated and passed through a plug ofNa₂SO₄ and the filtrate concentrated in vacuo. The residue was dissolvedin DMSO and purified by reverse-phase acidic HPLC to afford the desireddiastereomers as TFA adducts.

(rac)-(trans)-N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 22% isolated yield. LCMS (m/z) (M+H)=499.1, Rt=1.02 min; ¹H NMR (400MHz, DMSO-d6) δ ppm 10.77 (s, 1H) 9.01 (d, J=4.89 Hz, 1H) 8.36 (s, 1H)8.19 (dd, J=4.95, 1.16 Hz, 1H) 7.99 (d, J=1.34 Hz, 1H) 7.70-7.81 (m, 3H)7.40 (d, J=8.44 Hz, 1H) 3.85-4.05 (m, 3H) 3.55 (td, J=11.83, 2.63 Hz,1H) 3.35-3.47 (m, 1H) 3.24 (t, J=10.82 Hz, 1H) 2.96 (td, J=12.29, 3.42Hz, 1H) 2.26 (s, 3H) 1.94-2.06 (m, 1H) 1.84 (t, J=12.59 Hz, 1H) 1.57 (s,3H).

(rac)-(cis)-N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 16.4% isolated yield. LCMS (m/z) (M+H)=499.1, Rt=1.07 min; ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.59-10.95 (m, 1H) 8.88-9.11 (m, 1H) 8.36 (s,1H) 8.19 (dd, J=5.01, 1.10 Hz, 1H) 7.99 (d, J=1.34 Hz, 1H) 7.64-7.85 (m,3H) 7.31-7.51 (m, 2H) 3.92-4.06 (m, 2H) 3.76-3.90 (m, 1H) 3.42-3.66 (m,1H) 3.15-3.38 (m, 2H) 2.71-3.05 (m, 1H) 2.26 (d, J=1.96 Hz, 3H)1.79-2.09 (m, 1H) 1.50-1.69 (m, 4H).

The following compounds were prepared using methods from the aboveexamples, using annronriate starting materials:

Ex. No. Structure Name Physical Data 41

(rac)-(trans)-2-(1,1- difluoroethyl)-N- (3-(6-hydroxy-6-methyl-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin-9-yl)-4- methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm1H NMR (400 MHz, DMSO- d6) ä ppm 10.60-10.80 (m, 1 H) 8.76-9.06 (m, 1 H)8.12-8.28 (m, 1 H) 7.89-8.10 (m, 2 H) 7.63-7.87 (m, 3 H) 7.29-7.46 (m, 1H) 3.90- 4.00 (m, 3 H) 3.51-3.71 (m, 1 H) 3.38-3.51 (m, 1 H) 3.21-3.34(m, 1 H) 2.96 (td, J = 12.20, 3.36 Hz, 1 H) 2.23-2.27(m, 3 H) 2.06 (t, J= 19.13 Hz, 4 H) 1.79-1.88 (m, 1 H) 1.53-1.62 (m, 3 H); LCMS (m/z) (M +H) = 4954., Rt = 0.98 min. 42

(rac)-(cis)-2-(1,1- difluoroethyl)-N- (3-(6-hydroxy-6-methyl-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin-9-yl)-4- methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm10.67 (s, 1 H) 8.76-9.02 (m, 1 H) 8.17 (s, 1 H) 7.90-8.07 (m, 2 H)7.64-7.79 (m, 2 H) 7.24-7.47 (m, 2 H) 3.97 (br dd, J = 11.25, 3.06 Hz, 2H) 3.81-3.90 (m, 3 H) 3.58 (td, J = 11.74, 2.69 Hz, 1 H) 3.14-3.36 (m, 2H) 2.78 (td, J = 12.13, 3.61 Hz, 1 H) 2.25 (s, 3 H) 2.05 (t, J = 19.13Hz, 3 H) 1.51- 1.90 (m, 4 H); LCMS (m/z) (M + H) = 4954., Rt = 1.03 min.43

(rac)-(trans)-N-(5- (6-hydroxy-6- methyl-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80(s, 1 H) 8.90 (d, J = 2.45 Hz, 1 H) 8.26-8.38 (m, 2 H) 8.21 (d, J = 2.45Hz, 1 H) 8.08 (d, J = 1.34 Hz, 1H) 8.02 (dd, J = 7.82, 0.73 Hz, 1 H)7.83 (t, J = 7.83 Hz, 2 H) 3.88-4.07 (m, 3 H) 3.56 (td, J = 11.71, 2.63Hz, 1 H) 3.35-3.47 (m, 1 H) 3.16-3.30(m, 1 H) 2.95 (td, J = 12.26, 3.36Hz, 1 H) 2.47 (s, 3 H) 2.03 (dd, J = 12.84, 2.57 Hz, 1 H) 1.83 (t, J =12.65 Hz, 1 H) 1.56 (s, 3 H); LCMS (m/z) (M + H) = 495.4., Rt = 0.94min. 44

(rac)-(cis)-N-(5-(6- hydroxy-6-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.82(s, 1 H) 8.95 (d, J = 2.32 Hz, 1 H) 8.27-8.40 (m, 2 H) 8.19 (d, J = 2.32Hz, 1 H) 7.97- 8.06 (m, 2 H)7.83 (t, J = 7.83 Hz, 1 H) 7.45 (s, 1 H)3.98 (br dd, J = 11.55, 3.36 Hz, 5 H) 3.74-3.89 (m, 6 H) 3.59 (td, J =11.71, 2.63 Hz, 2 H) 3.15-3.37 (m, 2 H)2.78 (td, J = 12.10, 3.55 Hz, 1H) 1.86 (dd, J = 13.51, 2.26 Hz, 1 H) 1.48- 1.73 (m, 4 H); LCMS (m/z)(M + H) = 495.4, Rt = 1.00 min.

Example 45(rac)-N-(4-methyl-3-(2-methyl-3b,4,6,7-tetrahydro-2H-[1,4]oxazino[4,3-a]pyrazolo[4,3-c]quinolin-10-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinolin-6(4H)-one (1.0equiv.) was treated with DMF-DMA (15 equiv.) and the mixture heated at100° C. for 3 h and concentrated in vacuo. The residue was dissolved inEtOH (0.2M) and treated with methylhydrazine (5 equiv.). This mixturewas agitated at room temperature over 72 h to afford a yellowsuspension. The solvent was evaporated in vacuo and the residue waspurified by flash chromatography (0-50% EtOAc/heptane) to afford thedesired product10-bromo-2-methyl-3b,4,6,7-tetrahydro-2H-[1,4]oxazino[4,3-a]pyrazolo[4,3-c]quinolinein 13.2% isolated yield. LCMS (m/z) (M+H)=321.9, Rt=1.35 min.

Step 2:

10-bromo-2-methyl-3b,4,6,7-tetrahydro-2H-[1,4]oxazino[4,3-a]pyrazolo[4,3-c]quinoline(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.), 2.0 M Na₂CO₃ (2.5equiv.) were combined in dioxane (1.0 mL) and the mixture heated in MWat 130° C. for 30 min. The mixture was cooled to room temperature andthe organic layer was passed through short plug of anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by reverse phase HPLC toafford the desired product as free-base. LCMS (m/z) (M+H)=520.4, Rt=1.42min; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1H) 8.99 (d, J=5.01 Hz,1H) 8.37 (s, 1H) 8.20 (dd, J=5.01, 1.10 Hz, 1H) 7.63-7.77 (m, 3H)7.20-7.42 (m, 2H) 6.72-6.92 (m, 2H) 4.39 (dd, J=10.03, 3.30 Hz, 1H) 4.29(dd, J=11.19, 2.87 Hz, 1H) 4.12 (s, 3H) 3.95 (dd, J=10.88, 3.06 Hz, 1H)3.47-3.69 (m, 3H) 2.92 (td, J=11.74, 3.42 Hz, 1H) 2.27 (s, 3H).

Example 46(rac)(trans)-2-(1,1-difluoroethyl)-N-(3-(5-hydroxy-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide

Into a MW vial were charged2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.0 equiv.),2-chloro-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-5-ol(1.0 equiv.), K₃PO₄ (3.0 equiv.), X-Phos G2 Pd-cycle (0.1 equiv.) anddioxane:DMF:Water(5:1:1) (0.1 M). The vial was capped and agitated in MWat 130° C. for 30 min and the mixture was cooled to room temperature andthen diluted with EtOAc. The organic layer was passed through a plug ofMgSO₄ and the filtrate concentrated in vacuo. The residue was purifiedby reverse-phase basic HPLC to afford the desired product(trans)-2-(1,1-difluoroethyl)-N-(3-(5-hydroxy-5,6,6a,7,9,10-hexahydropyridazino[3′,4′:5,6]pyrido[2,1-c][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamideas free-base. LCMS (m/z) (M+H)=482.4, Rt=0.72 min. ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.69 (s, 1H) 8.88 (dd, J=5.01, 0.61 Hz, 1H) 8.19 (d,J=0.61 Hz, 1H) 8.04 (dd, J=5.01, 1.59 Hz, 1H) 7.71-7.83 (m, 2H) 7.35 (d,J=8.07 Hz, 1H) 6.96 (br s, 1H) 5.73 (br s, 1H) 4.79-5.00 (m, 1H)3.78-4.01 (m, 3H) 3.51 (td, J=11.71, 2.51 Hz, 2H) 3.29 (br s, 1H) 2.94(br s, 1H) 2.28 (s, 3H) 2.23 (ddd, J=12.81, 5.72, 3.48 Hz, 1H) 2.05 (t,J=19.13 Hz, 3H) 1.55-1.73 (m, 1H).

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

Ex. No. Structure Name Physical Data 47

(rac)-(trans)-N- (5-(5-hydroxy- 5,6,6a,7,9,10- hexahydropyri-dazino[3′,4′:5,6] pyrido[2,1- c][1,4]oxazin-2- yl)-6-methyl-pyridin-3-yl)-3- (trifluorometh- yl)benzamide ¹H NMR (400 MHz, DMSO-d6)δ ppm 10.51-10.84 (m, 1 H) 8.92 (d, J = 2.45 Hz, 1 H) 8.34 (s, 1 H) 8.30(d, J = 7.83 Hz, 1 H) 8.21 (d, J = 2.32 Hz, 1H) 8.00 (d, J = 7.83 Hz, 1H) 1.11-7.85 (m, 1 H) 7.07 (br s, 1 H) 5.76 (br s, 1 H) 4.83- 5.05 (m, 1H) 3.83-4.09 (m, 3 H) 3.44-3.68 (m, 2 H) 3.35(s, 1 H) 2.85-3.09 (m, 1 H)2.48-2.49 (m, 3 H) 2.23 (ddd, J = 12.93, 5.65, 3.30 Hz, 1 H) 1.67 (dt, J= 12.72, 10.64 Hz, 1 H); LCMS (m/z) (M + H) = 486.1, Rt = 0.92 min. 48

(rac)-(trans)-N- (3-(5-hydroxy- 5,6,6a,7,9,10- hexahydro- pyridazin-o[3′,4′:5,6]pyr- ido[2,1- c][1,4]oxazin- 2-yl)-4- methylphenyl)-2-(trifluorometh- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 15.05(br s, 1 H) 10.91 (s, 1 H) 9.02 (d, J = 5.01 Hz, 1 H) 8.32- 8.41 (m, 1H) 8.20 (dd, J = 4.95, 1.16 Hz, 1 H) 7.99 (d, J = 2.20 Hz, 1 H) 7.83(dd, J = 8.31, 2.20 Hz, 1 H) 7.38-7.53 (m, 2 H) 6.17 (br s, 1 H) 4.84(dd, J = 10.76, 5.14 Hz, 1 H) 4.26 (br d, J = 13.33 Hz, 1 H) 3.83-4.09(m, 3 H) 3.12-3.32 (m, 2 H) 2.15-2.39 (m, 4 H) 1.78 (dt, J = 12.84,10.45 Hz, 1 H); LCMS (m/z) (M + H) = 486.5, Rt = 1.10 min.

Example 49(rac)-N-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

Into a MW vial was added(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5,5-diyl)dimethanol(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), K₃PO₄ (51.7 mg, 0.244 mmol), X-Phos G2 Pd-Cycle (0.1equiv.) and dioxane:DMF:water (5:1:1) (0.1 M). The mixture was heated inMW at 120° C. for 20 min and then cooled to room temperature and theproduct extracted with EtOAc. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo and the residue purified byreverse-phase HPLC to afford the desired productN-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas free-base. LCMS (m/z) (M+H)=528.2, Rt=1.29 min. ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.61 (s, 1H) 8.99 (d, J=5.01 Hz, 1H) 8.36 (s, 1H) 8.19(dd, J=5.01, 1.10 Hz, 1H) 7.67 (dd, J=8.25, 2.26 Hz, 1H) 7.61 (d, J=2.20Hz, 1H) 7.28 (d, J=8.31 Hz, 1H) 7.01 (d, J=7.58 Hz, 1H) 6.77 (d, J=0.98Hz, 1H) 6.60 (dd, J=7.52, 1.28 Hz, 1H) 4.44-4.68 (m, 2H) 3.70-4.05 (m,3H) 3.35-3.56 (m, 6H) 3.11-3.29 (m, 1H) 2.87 (td, J=12.38, 3.36 Hz, 1H)2.52-2.71 (m, 2H) 2.23 (s, 3H).

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

50

(rac)-N-(3-(5,5- bis(hydroxymeth- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (1,1-difluoroeth-yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1 H) 8.87(d, J = 5.01 Hz, 1 H) 8.17 (s, 1 H) 8.02 (d, J = 5.01 Hz, 1 H) 7.68 (dd,J = 8.25, 2.26 Hz, 1H) 7.62 (d, J = 2.20 Hz, 1 H) 7.27 (d, J = 8.44 Hz,1 H) 7.01 (d, J = 7.58 Hz, 1 H) 6.77 (d, J = 1.10 Hz, 1 H) 6.60 (dd, J =7.52, 1.41 Hz, 1 H) 4.46-4.68 (m, 2 H) 3.83-4.05 (m, 2 H) 3.75 (dd, J =11.07, 2.75 Hz, 1 H) 3.36-3.53 (m, 6 H) 3.20 (dd, J = 10.70, 2.75 Hz, 1H) 2.87 (td, J = 12.35, 3.30 Hz, 1 H) 2.53-2.74 (m, 2 H) 2.23 (s, 3 H)2.05 (t, J = 19.13 Hz, 3 H); LCMS (m/z) (M + H) = 524.2, Rt = 1.26 min.51

(rac)-N-(5-(5,5- bis(hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-3-(trifluoro-methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (s, 1 H) 8.82 (d,J = 2.45 Hz, 1 H) 8.24-8.39 (m, 2 H) 7.91-8.03 (m, 2 H) 7.81 (t, J =7.82 Hz, 1 H)7.05 (d, J = 7.70 Hz, 1 H) 6.85 (d, J = 1.34 Hz, 1 H) 6.66(dd, J = 7.58, 1.47 Hz, 1 H) 4.39-4.74 (m, 1 H) 3.87-4.03 (m, 1 H) 3.76(dd, J = 11.13, 2.69 Hz, 1 H) 3.38-3.56 (m, 6 H) 3.21 (dd, J = 10.70,2.87 Hz, 1 H) 2.88 (td, J = 12.41, 3.30 Hz, 1 H) 2.53-2.75 (m, 2 H) 2.43(s, 3 H); LCMS (m/z) (M + H) = 528.1, Rt = 1.21 min.

Examples 52 and 53N-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide

N-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak afforded(R)—N-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H) 8.87 (d, J=5.13 Hz, 1H)8.17 (s, 1H) 8.03 (d, J=4.89 Hz, 1H) 7.68 (dd, J=8.25, 2.26 Hz, 1H) 7.62(d, J=2.20 Hz, 1H) 7.27 (d, J=8.31 Hz, 1H) 7.01 (d, J=7.58 Hz, 1H) 6.78(d, J=0.86 Hz, 1H) 6.60 (dd, J=7.52, 1.28 Hz, 1H) 4.44-4.69 (m, 2H)3.71-4.05 (m, 3H) 3.36-3.56 (m, 6H) 3.20 (dd, J=10.64, 2.69 Hz, 1H)2.82-2.99 (m, 1H) 2.52-2.71 (m, 2H) 2.23 (s, 3H) 2.05 (t, J=19.07 Hz,3H); LCMS: (m/z) (M+H)=524.2, Rt=1.26 min; and the second eluting peakafforded(S)—N-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H) 8.87 (d, J=5.13 Hz, 1H)8.17 (s, 1H) 8.03 (d, J=4.89 Hz, 1H) 7.68 (dd, J=8.25, 2.26 Hz, 1H) 7.62(d, J=2.20 Hz, 1H) 7.27 (d, J=8.31 Hz, 1H) 7.01 (d, J=7.58 Hz, 1H) 6.78(d, J=0.86 Hz, 1H) 6.60 (dd, J=7.52, 1.28 Hz, 1H) 4.44-4.69 (m, 2H)3.71-4.05 (m, 3H) 3.36-3.56 (m, 6H) 3.20 (dd, J=10.64, 2.69 Hz, 1H)2.82-2.99 (m, 1H) 2.52-2.71 (m, 2H) 2.23 (s, 3H) 2.05 (t, J=19.07 Hz,3H); LCMS: (m/z) (M+H)=524.2, Rt=1.26 min.

Example 54(rac)-N-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5,5-diyl)dimethanol(1.0 equiv.) was dissolved in THF (0.15 M) and cooled to 0° C. Then,butyllithium (0.95 equiv.) was added dropwise and the mixture agitatedfor 10 min. Then TsCl (1.0 equiv.) in THF was added and the mixtureagitated for 1 h during which the desired tosylate intermediate was seenas the major product by LCMS: (m/z) (M+H)=524.2, 1.26 min. Thenbutyllithium (0.95 equiv.) was added and the mixture heated at 60° C.for 3 h during which desired product appears to be the major adduct. Thereaction mixture was quenched by addition of water and the productextracted with EtOAc. The organic layer was dried (MgSO₄), and theproduct purified by flash chromatography (0-50% EtOAc/heptane) to affordthe desired product9-bromo-2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetane]in 79% isolated yield. LCMS: (m/z) (M+H)=311.9, Rt=1.36 min.

Step 2:

Into a MW vial was added9-bromo-2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetane](1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), K₃PO₄ (0.1 equiv.), X-Phos G2 Pd-Cycle (0.1 equiv.) andthen dioxane:water (10:1) (0.1 M) was added. The vial was capped and themixture was heated in MW at 120° C. for 20 min and then cooled to roomtemperature and the product extracted with EtOAc. The organic layer wasdried (Na₂SO₄), filtered and concentrated in vacuo and the residuepurified by reverse-phase HPLC to afford the desired productN-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)-2-(trifluoromethyl)isonicotinamideasfree base; LCMS: (m/z) (M+H)=510.1, Rt=1.40 min. ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.61 (s, 1H) 8.98 (d, J=5.01 Hz, 1H) 8.36 (s, 1H) 8.18(dd, J=4.89, 1.10 Hz, 1H) 7.67 (dd, J=8.19, 2.32 Hz, 1H) 7.61 (d, J=2.32Hz, 1H) 7.28 (d, J=8.44 Hz, 1H) 7.08 (d, J=7.70 Hz, 1H) 6.77 (d, J=1.22Hz, 1H) 6.64 (dd, J=7.58, 1.47 Hz, 1H) 4.48-4.67 (m, 2H) 4.26 (t, J=5.99Hz, 2H) 4.17 (dd, J=11.13, 2.93 Hz, 1H) 3.78-3.93 (m, 2H) 3.63 (t,J=10.94 Hz, 1H) 3.55 (td, J=11.68, 2.45 Hz, 1H) 3.36 (dd, J=10.70, 3.00Hz, 1H) 3.01-3.14 (m, 2H) 2.90 (td, J=12.38, 3.48 Hz, 1H) 2.22 (s, 3H).

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

55

(rac)-2-(1,1- difluoroethyl)-N- (4-methyl-3- (2,4,4a,6- tetrahydro-1H-spiro[[1,4]ox- azino[4,3- a]quinoline-5,3′- ¹H NMR (400 MHz, DMSO-d6) δppm 10.56 (s, 1 H) 8.87 (d, J = 5.01 Hz, 1 H) 8.17 (s, 1 H) 8.02 (dd, J= 5.01, 1.34 Hz, 1 H) 7.67 (dd, J = 8.25, 2.26 Hz, 1 H) 7.61 (d, J =2.20 Hz, 1 H) 7.26 (d, J = 8.44 Hz, 1 H) 7.08 (d, J = 7.58 Hz, 1 H) 6.77(d, J = 1.22 Hz, 1 H) 6.64 (dd, J = 7.58, 1.34 Hz, 1 H) 4.47-4.66oxetan]-9- (m, 2 H) 4.26 (t, J = 6.11 Hz, 2 H) 4.17 yl)phenyl)iso- (dd,J = 11.13, 2.93 Hz, 1 H) 3.84 (dd, nicotinamide J = 11.68, 2.26 Hz, 2 H)3.63 (t, J = 10.94 Hz, 1 H) 3.55 (td, J = 11.49, 2.08 Hz, 1 H) 3.36 (dd,J = 10.70, 3.00 Hz, 1 H) 2.98-3.14 (m, 2 H) 2.90 (td, J = 12.44, 3.61Hz, 1 H) 2.21 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H)LCMS (m/z) (M + H) =506.1, Rt = 1.39 min. 56

(rac)-N-(6-methyl- 5-(2,4,4a,6- tetrahydro-1H- spiro[[1,4]ox- azino[4,3-a]quinoline-5,3′- oxetan]-9- yl)pyridin-3-yl)-3- (trifluoromethyl) ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1 H) 8.81 (d, J = 2.57 Hz, 1 H)8.32 (s, 1 H) 8.28 (d, J = 7.95 Hz, 1 H) 7.92-8.03 (m, 2 H) 7.81 (t, J =7.83 Hz, 1 H) 7.12 (d, J = 7.58 Hz, 1 H) 6.84 (d, J = 1.22 Hz, 1 H) 6.69(dd, J = 7.58, 1.34 Hz, 1 H) 4.48-4.65 (m, 2 H) 4.26 (t, J = 5.93 Hz, 2H) 4.17 (dd, J = 11.19, 2.87 Hz, 1 H) 3.80-3.92 (m, 2 H) 3.63 benzamide(t, J = 11.00 Hz, 1 H) 3.55 (td, J = 11.71, 2.63 Hz, 1 H) 3.38 (dd, J =10.76, 3.06 Hz, 1 H) 3.01-3.16 (m, 2 H) 2.92 (td, J = 12.38, 3.48 Hz, 1H) 2.42 (s, 3 H)LCMS (/m/z) (M + H) = 528.1, Rt = 1.21 min.

Examples 57 and 582-(1,1-difluoroethyl)-N-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)isonicotinamide

2-(1,1-difluoroethyl)-N-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)isonicotinamidewas resolved by chiral SFC. The first eluting peak afforded(R)-2-(1,1-difluoroethyl)-N-(4-methyl-3-(1′,2′,4′,4a′-tetrahydro-6′H-spiro[oxetane-3,5′-[1,4]oxazino[4,3-a]quinolin]-9′-yl)phenyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.17 (s, 1H) 8.02 (dd, J=5.07, 1.41 Hz, 1H) 7.56-7.75 (m, 2H) 7.26 (d,J=8.44 Hz, 1H) 7.08 (d, J=7.58 Hz, 1H) 6.77 (d, J=1.22 Hz, 1H) 6.64 (dd,J=7.58, 1.47 Hz, 1H) 4.46-4.68 (m, 2H) 4.13-4.31 (m, 3H) 3.84 (dd,J=11.68, 2.26 Hz, 2H) 3.49-3.68 (m, 2H) 3.38 (d, J=3.06 Hz, 1H)2.99-3.14 (m, 2H) 2.90 (td, J=12.47, 3.55 Hz, 1H) 2.21 (s, 3H) 1.95-2.12(m, 3H).; LCMS: (m/z) (M+H)=506.1, Rt=1.39 min; and the second elutingpeak afforded(S)-2-(1,1-difluoroethyl)-N-(4-methyl-3-(1′,2′,4′,4a′-tetrahydro-6′H-spiro[oxetane-3,5′-[1,4]oxazino[4,3-a]quinolin]-9′-yl)phenyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.17 (s, 1H) 8.02 (dd, J=5.07, 1.41 Hz, 1H) 7.56-7.75 (m, 2H) 7.26 (d,J=8.44 Hz, 1H) 7.08 (d, J=7.58 Hz, 1H) 6.77 (d, J=1.22 Hz, 1H) 6.64 (dd,J=7.58, 1.47 Hz, 1H) 4.46-4.68 (m, 2H) 4.13-4.31 (m, 3H) 3.84 (dd,J=11.68, 2.26 Hz, 2H) 3.49-3.68 (m, 2H) 3.38 (d, J=3.06 Hz, 1H)2.99-3.14 (m, 2H) 2.90 (td, J=12.47, 3.55 Hz, 1H) 2.21 (s, 3H) 1.95-2.12(m, 3H).; LCMS: (m/z) (M+H)=506.1, Rt=1.39 min.

Example 59(rac)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

Into a MW vial was added(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), K₃PO₄ (2.0 equiv.), X-Phos G2 Pd-Cycle (0.1 equiv.) andthen dioxane:DMF:Water (5:1:0.2) (0.1 M) was added. The mixture washeated in MW at 120° C. for 20 min and then cooled to room temperatureand the product extracted with EtOAc. The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo and the residue purified byreverse-phase HPLC and then column chromatography (0-100% EtOAc/heptane)to afford the desired productN-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas4:1 diastereomeric mixture. LCMS: (m/z) (M+H)=498.4, Rt=1.34 min. ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.61 (s, 1H) 8.98 (d, J=5.01 Hz, 1H) 8.36 (s,1H) 8.19 (dd, J=4.95, 1.04 Hz, 1H) 7.67 (dd, J=8.19, 2.20 Hz, 1H)7.58-7.64 (m, 1H) 7.28 (d, J=8.44 Hz, 1H) 6.98-7.09 (m, 1H) 6.58-6.83(m, 2H) 3.94 (dd, J=11.19, 3.00 Hz, 1H) 3.74-3.90 (m, 2H) 3.46-3.71 (m,3H) 2.59-2.94 (m, 5H) 2.22 (s, 4H) 1.63-1.83 (m, 1H).

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

60

(rac)-2-(1,1- difluoroethyl)-N- (3-(5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methyl-phenyl)isonicotin- amide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1 H)8.87 (dd, J = 5.01, 0.61 Hz, 1 H) 8.17 (s, 1 H) 8.02 (dd, J = 5.01, 1.35Hz, 1 H) 7.52-7.78 (m, 2H) 7.27 (d, J = 8.44 Hz, 1 H) 6.99- 7.10 (m, 1H) 6.58-6.83 (m, 2 H) 4.55-4.78 (m, 1 H) 3.73-4.00 (m, 2 H) 3.44-3.72(m, 2 H) 3.35 (t, J = 5.50 Hz, 2 H) 3.22-3.29 (m, 1 H) 2.57- 2.90 (m, 4H) 2.22 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H) 1.67-1.84 (m, 1 H)); LCMS(m/z) (M + H) = 494.1, Rt = 1.34 min. 61

(rac)-N-(5-(5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)- 6-methylpyridin- 3-yl)-3-(trifluoro-methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (s, 1 H) 8.82 (d,J = 2.44 Hz, 1 H) 8.17-8.47 (m, 2 H) 7.95-8.07 (m, 2 H) 7.81 (t, J =7.83 Hz, 1H) 6.99-7.15 (m, 1 H) 6.62-6.90 (m, 2 H) 4.55-4.81 (m, 1 H)3.66-4.06 (m, 3 H) 3.46-3.64 (m, 1 H) 3.36 (t, J = 5.50 Hz, 2 H)3.22-3.29 (m, 1 H), 2.56- 3.00 (m, 4 H) 2.42 (s, 3 H) 1.68-2.16 (m, 1H); LCMS (m/z) (M + H) = 528.1, Rt = 1.21 min.

Examples 62 and 632-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

2-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamidewas resolved by chiral SFC to afford single enantiomers of eachdiastereomer. The first eluting peak affordedN-(3-((4aR,5R)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H) 8.87 (d, J=5.01 Hz, 1H) 8.17(s, 1H) 8.03 (d, J=4.65 Hz, 1H) 7.68 (dd, J=8.19, 2.20 Hz, 1H) 7.62 (d,J=2.08 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.62-6.75(m, 2H) 4.69 (t, J=5.14 Hz, 1H) 3.81-4.04 (m, 2H) 3.52-3.75 (m, 2H)3.34-3.39 (m, 2H) 3.22-3.28 (m, 1H) 2.76-2.93 (m, 2H) 2.57-2.69 (m, 2H)2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.70-1.84 (m, 1H); LCMS: (m/z)(M+H)=494.1, Rt=2.36 min (SQ4); and the fourth eluting peak affordedN-(3-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H) 8.87 (d, J=5.01 Hz, 1H) 8.17(s, 1H) 8.03 (d, J=4.65 Hz, 1H) 7.68 (dd, J=8.19, 2.20 Hz, 1H) 7.62 (d,J=2.08 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.62-6.75(m, 2H) 4.69 (t, J=5.14 Hz, 1H) 3.81-4.04 (m, 2H) 3.52-3.75 (m, 2H)3.34-3.39 (m, 2H) 3.22-3.28 (m, 1H) 2.76-2.93 (m, 2H) 2.57-2.69 (m, 2H)2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H) 1.70-1.84 (m, 1H); LCMS: (m/z)(M+H)=494.1, Rt=2.36 min (SQ4).

Examples 64 and 652-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Chiral SFC of2-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamideafforded second eluting peak asN-(3-((4aR,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideisonicotinamide; ¹H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H) 8.87 (d,J=5.01 Hz, 1H) 8.17 (s, 1H) 8.02 (d, J=5.01 Hz, 1H) 7.68 (dd, J=8.25,2.26 Hz, 1H) 7.61 (d, J=2.20 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 7.01 (d,J=7.58 Hz, 1H) 6.77 (d, J=1.10 Hz, 1H) 6.58-6.63 (m, 1H) 4.59 (t, J=4.89Hz, 1H) 3.71-3.90 (m, 3H) 3.43-3.64 (m, 3H) 2.63-2.95 (m, 3H) 2.22 (s,3H) 1.87-2.13 (m, 5H); LCMS: (m/z) (M+H)=494.1, Rt=2.34 min (SQ4); andthe third eluting peak affordedN-(3-((4aS,5R)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H) 8.87 (d, J=5.01 Hz, 1H) 8.17(s, 1H) 8.02 (d, J=5.01 Hz, 1H) 7.68 (dd, J=8.25, 2.26 Hz, 1H) 7.61 (d,J=2.20 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 7.01 (d, J=7.58 Hz, 1H) 6.77 (d,J=1.10 Hz, 1H) 6.58-6.63 (m, 1H) 4.59 (t, J=4.89 Hz, 1H) 3.71-3.90 (m,3H) 3.43-3.64 (m, 3H) 2.63-2.95 (m, 3H) 2.22 (s, 3H) 1.87-2.13 (m, 5H);LCMS: (m/z) (M+H)=494.1, Rt=2.34 min (SQ4).

Example 66(rac)-N-methyl-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide

Step 1:

Into a MW vial was added9-bromo-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), K₃PO₄ (2.0 equiv.), X-Phos G2 Pd-Cycle (0.1 equiv.) andthen dioxane:DMF:Water (5:1:0.2) (0.1 M). The mixture was heated in MWat 120° C. for 20 min and then cooled to room temperature and theproduct extracted with EtOAc. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo and the residue purified byreverse-phase HPLC to afford the desired productN-methyl-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamideas free-base in 33.3% isolated yield in 4:1 diastereomeric ratio. ¹H NMR(400 MHz, DMSO-d6) δ 10.63 (s, 1H) 8.99 (d, J=4.89 Hz, 1H) 8.36 (s, 1H)8.19 (dd, J=5.01, 0.98 Hz, 1H) 8.08 (q, J=4.40 Hz, 1H) 7.57-7.74 (m, 2H)7.28 (d, J=8.31 Hz, 1H) 7.04 (d, J=7.58 Hz, 1H) 6.78 (d, J=1.10 Hz, 1H)6.61-6.69 (m, 1H) 3.39-3.97 (m, 4H) 2.73-3.25 (m, 5H) 2.55-2.68 (m, 3H)2.39-2.47 (m, 1H) 2.16-2.26 (m, 3H) LCMS: (m/z) (M+H)=525.1, Rt=1.33min.

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

67

(rac)-9-(5-(2-(1,1- difluoroethyl)iso- nicotinamido)-2- methylphenyl)-N-methyl- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinoline-5-carboxamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.87 (d, J =5.14 Hz, 1 H) 8.17 (s, 1 H) 8.08 (q, J = 4.48 Hz, 1 H) 8.02 (d, J = 3.67Hz, 1 H) 7.68 (dd, J = 8.19, 2.20 Hz, 1 H) 7.61 (d, J = 2.20 Hz, 1 H)7.27 (d, J = 8.44 Hz, 1 H) 7.04 (d, J = 7.58 Hz, 1 H) 6.78 (d, J = 1.22Hz, 1 H) 6.61-6.68 (m, 1 H) 3.40-4.00 (m, 4 H) 2.73- 3.24 (m, 4 H)2.57-2.65 (m, 3 H) 2.37-2.47 (m, 1 H) 2.22 (s, 3 H) 2.05 (t, J = 19.13Hz, 3 H); LCMS (m/z) (M + H) = 521.2, Rt = 1.30 min. 68

(rac)-N-methyl- 9-(2-methyl-5-(3- (trifluorometh- yl)benzamido)pyr-idin-3-yl)- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinoline-5-carboxamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (br. s., 1 H) 8.98 (s,1 H) 8.26-8.40 (m, 3 H) 8.20 (br. s., 1 H) 8.09 (q, J = 4.40 Hz, 1 H)8.02 (d, J = 7.82 Hz, 1 H) 7.83 (t, J = 7.82 Hz, 1 H) 7.08-7.14 (m, 1 H)6.90 (s, 1 H) 6.74 (dd, J = 7.64, 1.53 Hz, 1 H) 3.63-4.00 (m, 20 H)3.35-3.58 (m, 5H) 2.74-3.24 (m, 8 H) 2.57-2.70 (m, 5 H) 2.38-2.46 (m, 2H); LCMS (m/z) (M + H) = 528.1, Rt = 1.21 min.

Examples 69 and 709-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide

Chiral SFC of9-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamideafforded separation of all four possible compounds. The first elutingpeak methyl(4aR,5R)-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate;¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H) 8.87 (d, J=5.01 Hz, 1H) 8.17(s, 1H) 8.03 (d, J=5.01 Hz, 1H) 7.89 (q, J=4.40 Hz, 1H) 7.57-7.75 (m,2H) 7.27 (d, J=8.44 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.77 (d, J=1.10 Hz,1H) 6.62 (dd, J=7.52, 1.41 Hz, 1H) 3.88 (d, J=13.08 Hz, 1H) 3.61-3.78(m, 2H) 3.41-3.55 (m, 3H) 2.97-3.10 (m, 1H) 2.73-2.92 (m, 3H) 2.62 (d,J=4.52 Hz, 3H) 2.23 (s, 3H) 2.05 (t, J=19.13 Hz, 3H); LCMS: (m/z)(M+H)=521.1, Rt=2.25 min (SQ4); and the second eluting peak methyl(4aS,5S)-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate;¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H) 8.87 (d, J=5.01 Hz, 1H) 8.17(s, 1H) 8.03 (d, J=5.01 Hz, 1H) 7.89 (q, J=4.40 Hz, 1H) 7.57-7.75 (m,2H) 7.27 (d, J=8.44 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.77 (d, J=1.10 Hz,1H) 6.62 (dd, J=7.52, 1.41 Hz, 1H) 3.88 (d, J=13.08 Hz, 1H) 3.61-3.78(m, 2H) 3.41-3.55 (m, 3H) 2.97-3.10 (m, 1H) 2.73-2.92 (m, 3H) 2.62 (d,J=4.52 Hz, 3H) 2.23 (s, 3H) 2.05 (t, J=19.13 Hz, 3H); LCMS: (m/z)(M+H)=521.1, Rt=2.25 min (SQ4).

Examples 71 and 729-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide

Chiral SFC of9-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamideafforded the third peak as methyl(4aS,5R)-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate;¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H) 8.78-8.95 (m, 1H) 8.17 (s, 1H)8.08 (q, J=4.36 Hz, 1H) 8.02 (dd, J=5.07, 1.41 Hz, 1H) 7.68 (dd, J=8.19,2.20 Hz, 1H) 7.62 (d, J=2.20 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 7.04 (d,J=7.58 Hz, 1H) 6.78 (d, J=1.10 Hz, 1H) 6.64 (dd, J=7.58, 1.34 Hz, 1H)3.89 (dd, J=11.25, 2.81 Hz, 1H) 3.67-3.82 (m, 2H) 3.53 (td, J=11.58,2.63 Hz, 1H) 3.04-3.22 (m, 2H) 2.90-3.01 (m, 1H) 2.72-2.84 (m, 2H) 2.63(d, J=4.65 Hz, 3H) 2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H); LCMS: (m/z)(M+H)=521.1, Rt=2.26 min (SQ4). The fourth eluting peak afforded methyl(4aR,5S)-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylate;¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H) 8.78-8.95 (m, 1H) 8.17 (s, 1H)8.08 (q, J=4.36 Hz, 1H) 8.02 (dd, J=5.07, 1.41 Hz, 1H) 7.68 (dd, J=8.19,2.20 Hz, 1H) 7.62 (d, J=2.20 Hz, 1H) 7.27 (d, J=8.44 Hz, 1H) 7.04 (d,J=7.58 Hz, 1H) 6.78 (d, J=1.10 Hz, 1H) 6.64 (dd, J=7.58, 1.34 Hz, 1H)3.89 (dd, J=11.25, 2.81 Hz, 1H) 3.67-3.82 (m, 2H) 3.53 (td, J=11.58,2.63 Hz, 1H) 3.04-3.22 (m, 2H) 2.90-3.01 (m, 1H) 2.72-2.84 (m, 2H) 2.63(d, J=4.65 Hz, 3H) 2.22 (s, 3H) 2.05 (t, J=19.13 Hz, 3H); LCMS: (m/z)(M+H)=521.1, Rt=2.26 min (SQ4).

Example 73(rac)-N-ethyl-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide

Step 1:

Into a Vial were charged9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (1.0 equiv.), EDC.HCl (1.2 equiv.), HOAT (1.2 equiv.), and DMF (0.3M). To the mixture was added DIEA (2.5 equiv.) followed by ethylamine(in THF) (1.2 equiv.) and the mixture agitated at room temperatureovernight. The next morning, the reaction mixture was diluted with EtOAcand washed with water and then with sat'd Na₂CO₃ and dried (MgSO₄),filtered and concentrated in vacuo and the residue9-bromo-N-ethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamidewas obtained in quantitative yield and was taken to the next step assuch. LCMS: (m/z) (M+H)=340.9, Rt=1.27 min.

Step 2:

Into a MW vial was added9-bromo-N-ethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide(1.0 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.), K₃PO₄ (2.0 equiv.), X-Phos G2 Pd-Cycle (0.1 equiv.) andthen dioxane:DMF:Water (5:1:0.2) (0.1 M). The mixture was heated in MWat 120° C. for 20 min and then cooled to room temperature and theproduct extracted with EtOAc. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo and the residue purified byreverse-phase HPLC to afford the desired productN-ethyl-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamideas free-base in 33.3% isolated yield in 5.5:1 diastereomeric ratio. ¹HNMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H) 8.99 (d, J=5.01 Hz, 1H) 8.36 (s,1H) 8.09-8.24 (m, 2H) 7.68 (dd, J=8.19, 2.32 Hz, 1H) 7.61 (d, J=2.32 Hz,1H) 7.28 (d, J=8.44 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.78 (d, J=1.10 Hz,1H) 6.64 (dd, J=7.58, 1.34 Hz, 1H) 3.89 (dd, J=11.19, 2.75 Hz, 1H)3.64-3.82 (m, 2H) 3.03-3.23 (m, 4H) 2.87-3.00 (m, 1H) 2.71-2.83 (m, 2H)2.38-2.47 (m, 1H) 2.22 (s, 3H) 1.05 (t, J=7.21 Hz, 3H) LCMS: (m/z)(M+H)=539.2, Rt=1.38 min.

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

Ex. No. Structure Name Physical Data 74

(rac)-9-(5-(2-(1,1- difluoroethyl)isonic- otinamido)-2- methylphenyl)-N-ethyl-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinoline-5-carboxamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.87 (d, J =5.01 Hz, 1 H) 8.08-8.22 (m, 2 H) 8.02 (d, J = 5.01 Hz, 1 H) 7.58-7.73(m, 2 H) 7.27 (d, J = 8.44 Hz, 1 H) 6.96- 7.08 (m, 1 H) 6.78 (d, J =0.98 Hz, 1 H) 6.57-6.66 (m, 1 H) 3.68-4.00 (m, 3 H) 3.43-3.60 (m, 1 H)3.03- 3.26 (m, 4 H) 2.86-3.00 (m, 1 H) 2.69-2.84 (m, 3 H) 2.38-2.46 (m,1 H) 2.22 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H) 1.05 (t, J = 7.27 Hz, 3H); LCMS (m/z) (M + H) = 535.2, Rt = 1.35 min 75

(rac)-N-ethyl-9-(2- methyl-5-(3- (trifluoromethyl) benzamido)pyridin-3-yl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinoline-5-carboxamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H) 8.82 (d, J =2.45 Hz, 1 H) 8.26 -8.37 (m, 2 H) 8.15 (t, J = 5.50 Hz, 1 H) 7.96-8.06(m, 2 H) 7.81 (t, J = 7.82 Hz, 1 H) 7.04- 7.12 (m, 1 H) 6.81-6.88 (m, 1H) 6.64-6.75 (m, 1 H) 3.64-3.98 (m, 3 H) 3.40-3.61 (m, 2 H) 2.90- 3.24(m, 4 H) 2.71-2.88 (m, 2 H) 2.36-2.46 (m, 4 H) 0.95-1.16 (m, 3 H) LCMS(m/z) (M + H) = 539.2, Rt = 1.29 min.

Examples 76 and 779-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-N-ethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide

Chiral SFC9-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-N-ethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamideafforded separation of all 4 compounds but only the two majorenantiomers were taken towards characterization and analysis. The firsteluting peak methyl(4aR,5R)—N-ethyl-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide;¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.10-8.21 (m, 2H) 8.02 (d, J=4.89 Hz, 1H) 7.59-7.74 (m, 2H) 7.27 (d,J=8.31 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.78 (d, J=0.73 Hz, 1H) 6.64 (dd,J=7.58, 1.22 Hz, 1H) 3.89 (dd, J=11.13, 2.57 Hz, 1H) 3.69-3.82 (m, 2H)3.53 (td, J=11.58, 2.38 Hz, 1H) 3.03-3.24 (m, 4H) 2.87-3.01 (m, 1H)2.70-2.82 (m, 2H) 2.44 (ddd, J=12.01, 9.81, 5.07 Hz, 1H) 2.22 (s, 3H)2.05 (t, J=19.13 Hz, 3H) 1.05 (t, J=7.21 Hz, 3H); LCMS: (m/z)(M+H)=535.1, Rt=2.39 min (SQ4); and the second eluting peak afforded(4aS,5S)—N-ethyl-9-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxamide;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.10-8.21 (m, 2H) 8.02 (d, J=4.89 Hz, 1H) 7.59-7.74 (m, 2H) 7.27 (d,J=8.31 Hz, 1H) 7.05 (d, J=7.58 Hz, 1H) 6.78 (d, J=0.73 Hz, 1H) 6.64 (dd,J=7.58, 1.22 Hz, 1H) 3.89 (dd, J=11.13, 2.57 Hz, 1H) 3.69-3.82 (m, 2H)3.53 (td, J=11.58, 2.38 Hz, 1H) 3.03-3.24 (m, 4H) 2.87-3.01 (m, 1H)2.70-2.82 (m, 2H) 2.44 (ddd, J=12.01, 9.81, 5.07 Hz, 1H) 2.22 (s, 3H)2.05 (t, J=19.13 Hz, 3H) 1.05 (t, J=7.21 Hz, 3H); LCMS: (m/z)(M+H)=535.1, Rt=2.39 min (SQ4).

Example 78(rac)-2-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Step 1:

(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol(111 mg, 0.35 mmol), PdCl₂(dppf).CH₂Cl₂ adduct (28.6 mg, 0.035 mmol),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.0 equiv.) were combined in Dioxane (0.1 M) and then 2.0 M Na₂CO₃ (2.0equiv.) was added. The mixture was heated in heated in a heating blockat 105° C. for 2 h. After the elapsed time, LCMS indicated formation ofdesired product. The reaction mixture was cooled to rt and thenextracted with EtOAc. The combined organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashchromatography (0-100% EtOAc/heptane) to afford the desired product.LCMS: (m/z) (M+H)=512.3, Rt=2.35 min (SQ4). ¹H NMR (400 MHz, DMSO-d6) δppm 10.58 (s, 1H) 8.87 (dd, J=5.07, 0.67 Hz, 1H) 8.17 (s, 1H) 8.02 (dd,J=4.95, 1.41 Hz, 1H) 7.68 (dd, J=8.25, 2.26 Hz, 1H) 7.57-7.65 (m, 1H)7.28 (d, J=8.44 Hz, 1H) 7.03-7.14 (m, 1H) 6.76-6.84 (m, 1H) 6.59-6.71(m, 1H) 5.28 (br s, 1H) 3.75-4.13 (m, 3H) 3.43-3.69 (m, 4H) 2.77-3.39(m, 8H) 2.23 (s, 3H) 1.94-2.13 (m, 3H).

The following compound of Example 79 was prepared using methods from theabove examples, using appropriate starting materials:

79

(rac)-2-(1,1- difluoroethyl)-N-(5- (5-fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6-methylpyridin-3- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm10.80 (s, 1 H) 8.90 (dd, J = 5.01, 0.61 Hz, 1 H) 8.83 (d, J = 2.45 Hz,1H) 8.20 (s, 1 H) 7.99-8.06 (m, 2 H) 7.04-7.21 (m, 1 H) 6.83-6.90 (m, 1H) 6.64-6.78 (m, 1 H) 5.08-5.43 (m, 1 H) 4.03 (dd, J = 11.19, 3.00 Hz, 1H) 3.75-3.97 (m, 2 H) 3.40-3.69 (m, 5 H) 2.76-3.39 (m, 10 H) 2.44 (s, 3H) 1.88- 2.13 (m, 3 H); LCMS (m/z) (M + H) = 513.2, Rt = 1.16 min.

Examples 80 and 812-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Chiral SFC of2-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamideafforded separation of all 4 compounds. The first eluting peak methyl2-(1,1-difluoroethyl)-N-(3-((4aS,5S)-5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H) 8.87 (d, J=5.01 Hz, 1H)8.18 (s, 1H) 8.03 (br d, J=4.65 Hz, 1H) 7.56-7.73 (m, 2H) 7.28 (d,J=8.31 Hz, 1H) 7.09 (d, J=7.58 Hz, 1H) 6.78 (s, 1H) 6.70 (d, J=7.58 Hz,1H) 5.29 (t, J=5.75 Hz, 1H) 4.03 (dd, J=11.19, 2.75 Hz, 1H) 3.73-3.92(m, 2H) 3.43-3.64 (m, 4H) 3.01-3.29 (m, 2H) 2.73-2.92 (m, 2H) 2.23 (s,3H) 2.05 (t, J=19.07 Hz, 3H); LCMS: (m/z) (M+H)=512.3, Rt=2.33 min(SQ8); the third eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,5R)-5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ (pm) 10.58 (s, 1H) 8.87 (d, J=4.89 Hz, 1H)8.18 (s, 1H) 8.03 (br d, J=4.77 Hz, 1H) 7.49-7.80 (m, 2H) 7.28 (d,J=8.31 Hz, 1H) 7.09 (d, J=7.58 Hz, 1H) 6.57-6.88 (m, 2H) 5.29 (br t,J=5.56 Hz, 1H) 4.03 (br dd, J=10.94, 2.38 Hz, 1H) 3.73-3.91 (m, 2H)3.41-3.65 (m, 4H) 2.99-3.29 (m, 2H) 2.73-2.94 (m, 2H) 2.23 (s, 3H) 2.05(t, J=19.07 Hz, 3H); LCMS: (m/z) (M+H)=512.3, Rt=2.33 min (SQ8).

Examples 82 and 832-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Chiral SFC of2-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamideafforded the second peak as2-(1,1-difluoroethyl)-N-(3-((4aS,5R)-5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H) 8.87 (d, J=5.50 Hz, 1H)8.17 (s, 1H) 8.02 (d, J=4.89 Hz, 1H) 7.59-7.77 (m, 2H) 7.28 (d, J=8.44Hz, 1H) 7.07 (d, J=7.70 Hz, 1H) 6.80 (d, J=1.10 Hz, 1H) 6.66 (dd,J=7.52, 1.41 Hz, 1H) 5.19 (t, J=5.75 Hz, 1H) 3.74-3.95 (m, 3H) 3.37-3.71(m, 5H) 2.78-3.11 (m, 3H) 2.23 (s, 3H) 2.05 (t, J=19.13 Hz, 3H); LCMS:(m/z) (M+H)=512.3, Rt=2.34 min (SQ8) and the fourth eluting fractionafforded2-(1,1-difluoroethyl)-N-(3-((4aR,5S)-5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H) 8.87 (br d, J=4.89 Hz,1H) 8.17 (s, 1H) 8.02 (br d, J=4.52 Hz, 1H) 7.49-7.73 (m, 2H) 7.28 (brd, J=8.19 Hz, 1H) 7.07 (br d, J=7.58 Hz, 1H) 6.80 (s, 1H) 6.66 (br d,J=7.46 Hz, 1H) 5.19 (br t, J=5.44 Hz, 1H) 3.78-4.04 (m, 3H) 3.39-3.76(m, 6H) 2.77-3.15 (m, 3H) 2.23 (s, 3H) 2.05 (br t, J=19.13 Hz, 3H););LCMS: (m/z) (M+H)=512.3, Rt=2.34 min (SQ8).

Examples 84 and 852-(1,1-difluoroethyl)-N-(5-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-yl)isonicotinamide

Chiral SFC2-(1,1-difluoroethyl)-N-(5-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-yl)isonicotinamideafforded separation of all 4 compounds but only the major enantiomericpair was taken towards characterization. The first eluting peak2-(1,1-difluoroethyl)-N-(5-((4aS,5S)-5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-yl)isonicotinamide.¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.80 (s, 1H) 8.90 (d, J=5.01 Hz, 1H)8.83 (d, J=2.32 Hz, 1H) 8.20 (s, 1H) 7.86-8.10 (m, 2H) 7.13 (d, J=7.58Hz, 1H) 6.86 (s, 1H) 6.75 (d, J=7.58 Hz, 1H) 5.75 (s, 1H) 5.30 (t,J=5.75 Hz, 1H) 4.03 (dd, J=11.13, 2.69 Hz, 1H) 3.78-3.93 (m, 2H)3.41-3.63 (m, 4H) 2.99-3.30 (m, 2H) 2.78-2.95 (m, 2H) 2.44 (s, 3H) 2.06(t, J=19.13 Hz, 3H); LCMS: (m/z) (M+H)=513.2, Rt=1.45 min (SQ8); thesecond eluting peak afforded2-(1,1-difluoroethyl)-N-(5-((4aR,5R)-5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-yl)isonicotinamide;¹H NMR (400 MHz, DMSO-d6) δ (pm) 10.58 (s, 1H) 8.87 (d, J=4.89 Hz, 1H)8.18 (s, 1H) 8.03 (br d, J=4.77 Hz, 1H) 7.49-7.80 (m, 2H) 7.28 (d,J=8.31 Hz, 1H) 7.09 (d, J=7.58 Hz, 1H) 6.57-6.88 (m, 2H) 5.29 (br t,J=5.56 Hz, 1H) 4.03 (br dd, J=10.94, 2.38 Hz, 1H) 3.73-3.91 (m, 2H)3.41-3.65 (m, 4H) 2.99-3.29 (m, 2H) 2.73-2.94 (m, 2H) 2.23 (s, 3H) 2.05(t, J=19.07 Hz, 3H); LCMS: (m/z) (M+H)=512.3, Rt=2.33 min (SQ8).

Example 86(rac)-N-(5-(5-cyano-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-yl)-2-(1,1-difluoroethyl)isonicotinamide

Into a vial were charged9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carbonitrile(1.0 equiv.),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.), Dioxane (0.1 M)and then 2M Na₂CO₃ (3.0 equiv.). The mixture was agitated at 100° C. ina heating block for 1 h and then the product was extracted with EtOAc.The organic layer was dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by flash chromatography (0-100%EtOAc/heptane) to afford the desired product as free base. LCMS: (m/z)(M+H)=503.2, Rt=1.47 min. ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.57 (s,1H) 8.87 (dd, J=5.01, 0.73 Hz, 1H) 8.18 (d, J=0.73 Hz, 1H) 8.03 (dd,J=5.01, 1.47 Hz, 1H) 7.71 (dd, J=8.25, 2.26 Hz, 1H) 7.64 (d, J=2.20 Hz,1H) 7.29 (d, J=8.44 Hz, 1H) 7.08 (d, J=7.70 Hz, 1H) 6.89 (d, J=1.10 Hz,1H) 6.74 (dd, J=7.64, 1.41 Hz, 1H) 4.19 (dd, J=11.31, 3.12 Hz, 1H)3.81-4.03 (m, 2H) 3.58 (td, J=11.77, 2.63 Hz, 1H) 3.36-3.44 (m, 1H)2.97-3.14 (m, 3H) 2.77 (td, J=12.10, 3.67 Hz, 1H) 2.24 (s, 3H) 2.05 (t,J=19.13 Hz, 3H) 1.43 (s, 3H).

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

Ex. No. Structure Name Physical Data 87

(rac)-N-(5-(5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9- yl)-6- methylpyridin-3- yl)-2-(1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s,1 H) 8.90 (dd, J = 5.07, 0.67 Hz, 1 H) 8.84 (d, J = 2.45 Hz, 1 H) 8.21(dd, J = 1.47, 0.86 Hz, 1 H) 7.91-8.09 (m, 2 H) 7.12 (d, J = 7.58 Hz, 1H) 6.97 (d, J = 1.34 Hz, 1 H) 6.79 (dd, J = 7.70, 1.47 Hz, 1 H) 4.20(dd, J = 11.25, 3.18 Hz, 1 H) 3.84- 4.03 (m, 2H) 3.58 (td, J = 11.77,2.63 Hz, 1 H) 3.39 (t, J = 10.94 Hz, 1 H) 2.95-3.17 (m, 3 H) 2.79 (td, J= 12.07, 3.61 Hz, 1 H) 2.44 (s, 3 H) 1.96-2.12 (m, 3 H) 1.44 (s, 3 H)LCMS (m/z) (M + H) = 504.1, Rt = 1.29 min 88

(rac)-N-(3-(5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9- yl)-4- methylphenyl)- 2-(1,1-difluoroethyl) isonictinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm10.51-10.65 (m, 1 H) 8.87 (dd, J = 5.07, 0.67 Hz, 1 H) 8.18 (d, J = 0.61Hz, 1 H) 8.02 (dd, J = 5.07, 1.53 Hz, 1H) 7.69 (dd, J = 8.25, 2.26 Hz, 1H) 7.63 (d, J = 2.32 Hz, 1 H) 7.28 (d, J = 8.44 Hz, 1 H) 7.08 (d, J =7.70 Hz, 1 H) 6.89 (d, J = 1.34 Hz, 1 H) 6.72 (dd,J = 7.58, 1.47 Hz, 1H) 3.84-4.08 (m, 3 H) 3.34-3.64 (m, H) 2.81-3.00 (m, 2 H) 2.22 (s, 3 H)2.05 (t, J = 19.13 Hz, 3 H) 1.35 (s, 3 H); LCMS (m/z) (M + H) = 503.1,Rt = 1.52 min. 89

(rac)-N-(5-(5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9- yl)-6- methylpyridin-3- yl)-2-(1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s,1 H) 8.85-9.01 (m, 2 H) 8.16-8.26 (m, 2 H) 8.05 (dd, J = 5.07, 1.53 Hz,1 H) 7.15 (d, J = 7.70 Hz, 1H) 7.02 (d, J = 1.34 Hz, 1 H) 6.82 (dd, J =7.64, 1.41 Hz, 1 H) 3.84-4.03 (m, 9 H) 3.31-3.58 (m, 5 H) 2.82-3.04 (m,2 H) 2.06 (t, J = 19.20 Hz, 3 H)1.36 (s, 3 H); LCMS (m/z) (M + H) =504.1, Rt = 1.33 min. 90

(rac)-N-(3-(5- cyano- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9- yl)-4- methylphenyl)- 2-(1,1- difluoroethyl)isonicotinamid LCMS: (m/z) (M + H) = 489.1, Rt = 1.47 min. ¹H NMR (400MHz, DMSO-d6) δ (ppm) 10.58 (s, 1 H) 8.87 (dd, J = 5.01, 0.61 Hz, 1 H)8.17 (d, J = 0.73 Hz, 1 H) 8.02 (dd, J = 5.01, 1.47 Hz, 1 H) 7.69 (dd, J= 8.19, 2.20 Hz, 1 H) 7.62 (d, J = 2.32 Hz, 1 H) 7.28 (d, J = 8.44 Hz, 1H) 7.11 (d, J = 7.70 Hz, 1 H) 6.83 (d, J = 1.22 Hz, 1 H) 6.72 (dd, J =7.58, 1.47 Hz, 1 H) 3.98-4.10 (m, 1 H) 3.92 (dd, J = 11.25, 2.81 Hz, 1H) 3.76 (br d, J = 11.98 Hz, 1 H) 3.57 (td, J = 11.55, 2.69 Hz, 1 H)3.36- 3.50 (m, 1H) 3.23-3.31 (m, 2 H) 3.05-3.20 (m, 2 H) 2.82 (td, J =11.98, 3.55 Hz, 1 H) 2.21 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H). 91

(rac)-N-(5-(5- cyano- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9- yl)-6- methylpyridin-3- yl)-2-(1,1- difluoroethyl)isonicotinamide 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (s, 1 H) 8.88-9.03(m, 2 H) 8.15-8.31 (m, 2 H) 8.05 (dd, J = 5.07, 1.53 Hz, 1 H) 7.18 (d, J= 7.70 Hz, 1H) 6.96 (d, J = 1.34 Hz, 1 H) 6.82 (dd, J = 7.58, 1.47 Hz, 1H) 4.02 (dd, J = 10.94, 2.02 Hz, 1 H) 3.94 (br dd, J = 11.31, 2.87 Hz, 1H) 3.78 (br d, J = 12.10 Hz, 1 H) 3.57 (td, J = 11.55, 2.69 Hz, 1 H)3.39- 3.46 (m, 1 H) 3.24-3.37 (m, 2 H) 3.09-3.21 (m, 2 H) 2.85 (td, J =12.04, 3.55 Hz, 1 H) 2.06 (t, J = 19.20 Hz, 3 H); LCMS (m/z) (M + H) =490.5, Rt = 1.31 min.

Examples 92 and 93N-(3-(5-amino-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide

Into a MW vial was charged PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.0 equiv.), tert-butyl(9-bromo-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)carbamate(1.0 equiv.) and then dioxane (0.2 M) and then 2.0 M Na₂CO₃ (2.5 equiv.)was added. The mixture was agitated in MW at 120° C. for 30 min and thendiluted with EtOAc. The organic layer was separated and dried andtreated with MeOH (0.1 M) and 4 N HCl in dioxane (40.0 equiv.) andagitated at room temperature for 4 h and concentrated in vacuo. Theresidue was dissolved in DMSO and purified by reverse phase HPLC (duringwhich separation of the two diastereomers was observed) and then byacidic method to afford the desired product as TFA adduct.

(rac)-(syn)-N-(3-(5-amino-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide((3.1% Isolated Yield)

LCMS: (m/z) (M+H)=493.1, Rt=1.65 min (SQ4). ¹H NMR (400 MHz, DMSO-d6) δ(ppm) 10.60 (s, 1H) 8.74-8.97 (m, 1H) 8.14 (br d, J=16.26 Hz, 4H) 8.02(dd, J=5.01, 1.47 Hz, 1H) 7.57-7.82 (m, 2H) 7.29 (d, J=8.44 Hz, 1H) 7.12(d, J=7.70 Hz, 1H) 6.94 (d, J=1.10 Hz, 1H) 6.74 (dd, J=7.58, 1.34 Hz,1H) 3.75-4.11 (m, 3H) 3.49-3.60 (m, 2H) 2.79-3.06 (m, 3H) 2.23 (s, 3H)2.05 (t, J=19.13 Hz, 3H) 1.29 (s, 3H).

(rac)-(anti)-N-(3-(5-amino-5-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide((3.0% Isolated Yield)

LCMS: (m/z) (M+H)=493.1, 1.66 min (SQ4). ¹H NMR (400 MHz, DMSO-d6) δ(ppm) 10.62 (s, 1H) 8.88 (d, J=5.14 Hz, 1H) 8.16 (d, J=0.73 Hz, 1H)7.90-8.12 (m, 3H) 7.76 (d, J=2.32 Hz, 1H) 7.58 (dd, J=8.19, 2.32 Hz, 1H)7.27-7.34 (m, 1H) 7.12 (d, J=7.70 Hz, 1H) 6.94 (s, 1H) 6.81 (dd, J=7.64,1.41 Hz, 1H) 3.77-4.16 (m, 3H) 3.48 (br d, J=11.13 Hz, 3H) 3.24 (br dd,J=11.13, 3.67 Hz, 2H) 2.72-3.18 (m, 4H) 2.18-2.30 (m, 3H) 1.95-2.17 (m,3H) 1.24-1.42 (m, 3H); MH+=493.1, Rt=1.66 min.

Example 94(rac)-N-(4-methyl-3-(8-oxo-2,4,4a,5,6,8-hexahydro-1H-pyrido[2′,1′:2,3]pyrimido[6,1-c][1,4]oxazin-10-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

10-bromo-4,4a,5,6-tetrahydro-1H-pyrido[2′,1′:2,3]pyrimido[6,1-c][1,4]oxazin-8(2H)-one(1.0 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) were combined in Dioxane (0.1 M) and then 2.0 M Na₂CO₃ (2.5equiv.) was added. The mixture was agitated in MW at 130° C. for 40 minand then the product extracted with EtOAc. The organic layer was passedthrough a plug of anhydrous Na₂SO₄, and the filtrate concentrated invacuo and the residue was purified by reverse-phase HPLC to afford thedesired productN-(4-methyl-3-(8-oxo-2,4,4a,5,6,8-hexahydro-1H-pyrido[2′,1′:2,3]pyrimido[6,1-c][1,4]oxazin-10-yl)phenyl)-2-(trifluoromethyl)isonicotinamideasa free-base. LCMS: (m/z) (M+H)=485.1, Rt=1.28 min. ¹H NMR (400 MHz,DMSO-d6) δ (ppm) 10.66 (s, 1H) 8.99 (d, J=5.01 Hz, 1H) 8.36 (s, 1H) 8.19(dd, J=4.95, 1.16 Hz, 1H) 7.58-7.74 (m, 2H) 7.29 (d, J=8.19 Hz, 1H) 5.63(d, J=1.59 Hz, 1H) 5.54 (d, J=1.47 Hz, 1H) 3.91-4.03 (m, 2H) 3.74-3.89(m, 2H) 3.63 (br d, J=13.08 Hz, 1H) 3.53 (td, J=11.68, 2.69 Hz, 1H)3.33-3.40 (m, 1H) 3.27 (d, J=10.76 Hz, 2H) 3.07 (td, J=12.35, 3.55 Hz,1H) 2.27 (s, 3H) 1.96-2.12 (m, 1H) 1.55-1.70 (m, 1H).

The following compound was prepared using methods from the aboveexamples, using appropriate starting materials

95

(rac)-2-(1,1- difluoroethyl)-N- (4-methyl-3-(8- oxo-2,4,4a,5,6,8-hexahydro-1H- pyrido[2′,1′:2,3] pyrimido [6,1- c][1,4]oxazin-10-yl)phenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (s, 1H) 8.88 (dd, J = 5.07, 0.67 Hz, 1 H) 8.17 (d, J = 0.61 Hz, 1 H) 8.02(dd, J = 5.07, 1.53 Hz, 1 H) 7.63- 7.73 (m, 2 H) 7.28 (d, J = 8.31 Hz, 1H) 5.63 (d, J = 1.59 Hz, 1 H) 5.54 (d, J = 1.47 Hz, 1 H) 3.90-3.99 (m, 2H) 3.76-3.88 (m, 2 H) 3.63 (br d, J = 12.96 Hz, 1 H) 3.53 (td, J =11.68, 2.69 Hz, 1 H) 3.33-3.41 (m, 1 H) 3.22-3.31 (m, 2 H) 3.07 (td, J =12.32, 3.48 Hz, 1 H) 2.26 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H) 1.56-1.69(m, 1 H).; LCMS (m/z) (M + H) = 485.1, Rt = 1.25 min.

Example 96(rac)-2-(1,1-difluoroethyl)-N-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)isonicotinamide

2-(1,1-difluoroethyl)isonicotinic acid (1 equiv.),10-(5-amino-2-methylpyridin-3-yl)-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol(1.0 equiv.), EDC.HCl (1.2 equiv.), HOAT (1.2 equiv.) in DMF (0.1 M)were stirred at inert atmosphere for 1 h. The reaction mixture was firstpurified by flash chromatography over silica gel (DCM with 10% MeOH) togive the >90% pure desired racemate and diastereomeric product2-(1,1-difluoroethyl)-N-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)isonicotinamide(49%). ¹H NMR (400 MHz, Methanol-d4) δ 8.87-8.78 (m, 2H), 8.21 (s, 1H),8.06 (d, J=2.5 Hz, 1H), 7.98 (dd, J=5.1, 1.5 Hz, 1H), 7.38 (dd, J=7.7,0.7 Hz, 1H), 6.63 (dd, J=7.6, 1.5 Hz, 1H), 6.56 (d, J=1.3 Hz, 1H),4.81-4.75 (m, 1H), 3.93-3.71 (m, 6H), 3.51-3.44 (m, 1H), 2.48 (s, 3H),2.33-2.16 (m, 2H), 2.09-1.95 (m, 5H). LCMS (m/z) (M+H)=495.2, Rt=0.95min.

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

97

2-(1,1- difluoroethyl)-N- (5-((5aR,7S)-7- hydroxy - 1,2,5,5a,6,7-hexahydro-4H- [1,4]oxazepino[4,5- a]quinolin-10-yl)-6- methylpyridin-3-yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.85-8.76 (m, 2H),8.25-8.17 (m, 1H), 8.06 (d, J = 2.5 Hz, 1H), 8.02-7.94 (m, 1H), 7.38(dd, J = 7.7, 0.7 Hz, 1H), 6.63 (dd, J = 7.6, 1.5 Hz, 1H), 6.56 (d, J =1.3 Hz, 1H), 4.83-4.79 (m, 1H), 3.95- 3.71 (m, 6H), 3.52-3.41 (m, 1H),2.48 (s, 3H), 2.32-2.16 (m, 2H), 2.12-1.94 (m, 5H). LCMS (m/z) (M + H) =495.2, Rt = 0.95 min. 98

2-(1,1- difluoroethyl)-N- (5-((5aS,7R)-7- hydroxy- 1,2,5,5a,6,7-hexahydro-4H- [1,4]oxazepino[4,5- a]quinolin-10-yl)-6- methylpyridin-3-yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.85-8.77 (m, 2H),8.24-8.17 (m, 1H), 8.06 (d, J = 2.5 Hz, 1H), 8.01-7.94 (m, 1H), 7.38(dd, J = 7.7, 0.8 Hz, 1H), 6.63 (dd, J = 7.6, 1.5 Hz, 1H), 6.56 (d, J =1.4 Hz, 1H), 4.83-4.80 (m, 1H), 3.93- 3.71 (m, 6H), 3.51-3.42 (m, 1H),2.48 (s, 3H), 2.34-2.13 (m, 2H), 2.11-1.93 (m, 5H). LCMS (m/z) (M + H) =495.2, Rt = 0.95 min.

Example 99(rac)-(cis)2-(1,1-difluoroethyl)-N-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)isonicotinamide

Step 1:

Into a vial were charged(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol(1.0 equiv.) and DCM. The mixture was cooled to 0° C. and Et₃N (3.0equiv.) was added. To the mixture was then added MsCl (1.1 equiv.) andthe mixture agitated for 30 min and then quenched by addition of waterand Sat'd NH₄Cl. The product was extracted with DCM. The organic layerwas separated and dried (MgSO₄), filtered and concentrated in vacuo toafford the crude product(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methylmethanesulfonate in quantitative yield. LCMS (m/z) (M+H)=333.2, Rt=0.86min.

Step 2:

(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methylmethanesulfonate (1.0 equiv.) was dissolved in DMF (0.1 M) and treatedwith NaSMe (1.5 equiv.). The mixture was agitated at room temperaturefor 30 min after which the mixture was quenched with sat'd NaHCO₃ andwater and the product extracted with EtOAc. The organic layer was dried(MgSO₄), filtered and concentrated in vacuo to afford the crude product9-chloro-5-((methylthio)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine,which was taken to the next step as such. LCMS (m/z) (M+H)=285.2,Rt=0.95 min.

Step 3:

9-chloro-5-((methylthio)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(1.0 equiv.) was dissolved in DMF (0.2 M) and treated with oxone (2.5equiv.). The mixture was agitated at room temperature for 45 min uponwhich LCMS indicated complete formation of desired product. The mixturewas diluted with EtOAc and filtered through celite. The filtrate waswashed with water twice and then dried (MgSO₄), filtered andconcentrated in vacuo. The residue9-chloro-5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridinewas obtained in 33% isolated yield was taken to the next step as suchwithout any further purification. LCMS (m/z) (M+H)=317.3, Rt=0.74 min.

Step 4:

9-chloro-5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(1.0 equiv.), X-Phos-Pd-Cycle-G2 (0.1 equiv.),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.0 equiv.) and K₃PO₄ (3.0 equiv.) were combined in dioxane: water(10:1) (0.1 M). The mixture was agitated in MW at 130° C. for 40 min andthen the product extracted with EtOAc. The organic layer was passedthrough a plug of anhydrous Na₂SO₄, and the filtrate concentrated invacuo. The residue was purified by reverse-phase HPLC to afford thedesired product2-(1,1-difluoroethyl)-N-(4-methyl-3-(5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)phenyl)isonicotinamideas a free-base. LCMS (m/z) (M+H)=557.3, Rt=0.79 min. 1H NMR (400 MHz,DMSO-d6) δ (ppm) 10.63 (s, 1H) 8.88 (dd, J=5.01, 0.61 Hz, 1H) 8.18 (d,J=0.61 Hz, 1H) 8.03 (dd, J=5.01, 1.59 Hz, 1H) 7.83 (d, J=1.34 Hz, 1H)7.73 (dd, J=8.31, 2.32 Hz, 1H) 7.66 (d, J=2.20 Hz, 1H) 7.32 (d, J=8.44Hz, 1H) 7.21 (br s, 1H) 4.05 (dd, J=11.19, 2.75 Hz, 1H) 3.79-3.91 (m,2H) 3.52 (td, J=11.62, 2.45 Hz, 1H) 3.40-3.47 (m, 1H) 3.10-3.27 (m, 4H)3.06 (s, 3H) 2.79-2.97 (m, 2H) 2.23 (s, 3H) 2.05 (t, J=19.13 Hz, 3H).

Example 100(rac)-(cis)-9-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicAcid

A mixture of9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (1.0 equiv.),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.1 equiv.), PdCl₂(dppf).CH₂Cl₂ adduct (0.1 equiv.) and 2 M Na₂CO₃ (3equiv.) in Dioxane (0.16 M, degassed) was irradiated in a microwave for1 h at 110° C. The cooled reaction mixture was quickly run through flashchromatography over silica gel (EtOAc with 50% MeOH). It was thenpurified via reverse phase BASIC prep-HPLC. The pure fractions werelyophilized to give the desired final racemate and diastereomericproduct,(rac)-9-(5-(2-(1,1-difluoroethyl)isonicotinamido)-2-methylphenyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline-5-carboxylicacid (34%). ¹H NMR (400 MHz, Methanol-d4) δ 8.83-8.75 (m, 1H), 8.17 (s,1H), 7.99-7.91 (m, 1H), 7.62 (ddd, J=7.9, 5.6, 2.3 Hz, 1H), 7.52 (dd,J=4.8, 2.4 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.05 (d, J=7.6 Hz,1H),6.81-6.74 (m, 1H), 6.67 (dd, J=7.6, 1.4 Hz, 1H), 4.03 (dd, J=11.1,2.7 Hz, 1H), 3.99-3.92 (m, 1H), 3.87-3.78 (m, OH), 3.76-3.64 (m, 2H),3.62-3.56 (m, OH), 3.42-3.34 (m, 1H), 3.22 (td, J=9.8, 3.0 Hz, 1H), 2.55(ddd, J=11.0, 9.4, 5.4 Hz, 1H), 2.24 (s, 3H), 2.03 (t, J=18.7 Hz, 3H).LCMS (m/z) (M+H)=508.1, Rt=0.87 min.

Example 101rac-cis-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A vial was charged with9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(1 equiv),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.2 equiv), and PdCl₂(dppf)-CH₂Cl₂ (0.1 equiv), potassium carbonate (3equiv), and 3:1 1,4-dioxane/water (0.2 M). The was sealed and heated to80° C. overnight. In the morning, the mixture was cooled and extractedwith EtOAc (3×). The combined organic extracts were concentrated invacuo. The residue was purified by chromatography on silica gel (50-100%EtOAc/heptane) to giveN-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(65.5% yield) as a white foam. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s,1H) 8.99 (d, J=5.01 Hz, 1H) 8.36 (s, 1H) 8.19 (dd, J=4.95, 1.04 Hz, 1H)7.91 (d, J=1.71 Hz, 1H) 7.73 (dd, J=8.25, 2.26 Hz, 1H) 7.65 (d, J=2.20Hz, 1H) 7.34 (d, J=8.44 Hz, 1H) 7.17 (d, J=1.71 Hz, 1H) 5.22 (d, J=3.55Hz, 1H) 4.77 (ddd, J=10.73, 6.76, 3.55 Hz, 1H) 3.82-3.95 (m, 2H) 3.75(d, J=11.37 Hz, 1H) 3.50-3.64 (m, 1H) 3.21-3.29 (m, 2H) 2.66-2.76 (m,1H) 2.24 (s, 3H) 2.06-2.19 (m, 1H) 1.54-1.65 (m, 1H). LCMS (m/z)(M+H)=485.3, Rt=0.99 min.

Examples 102 and 103N-(3-((4aR,6R)-6-Hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideandN-(3-((4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

rac-N-(3-(6-Hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas subjected to chiral SFC. The first eluting peak affordedN-(3-((4aR,6R)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid. The second eluting peak affordedN-(3-((4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid. NMR and LCMS data for each enantiomer matched that ofthe racemate.

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

104

rac-cis-N-(5-(6- Hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3- (trifluoromethyl)¹H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1 H) 8.83-8.91 (m, 1 H)8.25-8.36 (m, 2 H) 7.94-8.11 (m, 3 H) 7.73-7.86 (m, 1 H) 7.25 (d, J =1.59 Hz, 1 H) 5.26 (d, J = 3.67 Hz, 1 H) 4.72-4.84 (m, 1 H) 3.72- 3.95(m, 3 H) 3.47-3.63 (m, 1 H) 3.22-3.29 (m, 2 H) 2.65-2.83 (m, 1 H) 2.44(s, 3 H) 2.09-2.19 (m, 1 H) 1.53-1.66 (m, 1 H). LCMS benzamide (m/z)(M + H) = 485.3, Rt = 0.89 min 105

N-(5-((4aR,6R)-6- Hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3- (trifluoromethyl)66 (m, 1 H). LCMS (m/z) (M + H) = 485.3, Rt = 0.89 min benzamide 106

N-(5-((4aS,6S)-6- Hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3- (trifluoromethyl)66 (m, 1 H). LCMS (m/z) (M + H) = 485.3, Rt = 0.89 min benzamide 107

rac-cis-2-(1,1- Difluoroethyl)-N- (3-(6-hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- n-9-yl)-4-methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s,1 H) 8.88 (d, J = 4.52 Hz, 1 H) 8.18 (s, 1 H) 8.03 (d, J = 4.89 Hz, 1 H)7.91 (d, J = 1.59 Hz, 1 H) 7.73 (dd, J = 8.31, 2.20 Hz, 1 H) 7.65 (d, J= 2.20 Hz, 1 H) 7.33 (d, J = 8.44 Hz, 1 H) 7.17 (d, J = 1.59 Hz, 1 H)5.22 (d, J = 3.30 Hz, 1 H) 4.63- 4.86 (m, 1 H) 3.81-3.97 (m, 2 H) 3.75(d, J = 11.98 Hz, 1 H) 3.56 (td, J = 11.71, 2.75 Hz, 1 H) 3.19-3.29 (m,2 H) 2.63-2.80 (m, 1 H) 2.24 (s, 3 H) 2.14 (dd, J = 11.07, 6.66 Hz, 1 H)1.99-2.11 (m, 3 H) 1.59 (d, J = 11.86 Hz, 1 H). LCMS (m/z) (M + H) =481.3, Rt = 0.96 min. 108

2-(1,1- Difluoroethyl)-N- (3-((4aR,6R)-6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- n-9-yl)-4-methylphenyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1 H) 8.88 (d, J= 4.52 Hz, 1 H) 8.18 (s, 1 H) 8.03 (d, J = 4.89 Hz, 1 H) 7.91 (d, J =1.59 Hz, 1 H) 7.73 (dd, J = 8.31, 2.20 Hz, 1 H) 7.65 (d, J = 2.20 Hz, 1H) 7.33 (d, J = 8.44 Hz, 1 H) 7.17 (d, J = 1.59 Hz, 1 H) 5.22 (d, J =3.30 Hz, 1 H) 4.63- 4.86 (m, 1 H) 3.81-3.97 (m, 2 H) 3.75 (d, J = 11.98Hz, 1 H) 3.56 (td, isonicotinamide J = 11.71, 2.75 Hz, 1 H) 3.19-3.29(m, 2 H) 2.63-2.80 (m, 1 H) 2.24 (s, 3 H) 2.14 (dd, J = 11.07, 6.66 Hz,1 H) 1.99-2.11 (m, 3 H) 1.59 (d, J = 11.86 Hz, 1 H). LCMS (m/z) (M + H)= 481.3, Rt = 0.96 min. 109

2-(1,1- difluoroethyl)-N- (3-((4aS,6S)-6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- n-9-yl)-4-methylphenyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1 H) 8.88 (d, J= 4.52 Hz, 1 H) 8.18 (s, 1 H) 8.03 (d, J = 4.89 Hz, 1 H) 7.91 (d, J =1.59 Hz, 1 H) 7.73 (dd, J = 8.31, 2.20 Hz, 1 H) 7.65 (d, J = 2.20 Hz, 1H) 7.33 (d, J = 8.44 Hz, 1 H) 7.17 (d, J = 1.59 Hz, 1 H) 5.22 (d, J =3.30 Hz, 1 H) 4.63- 4.86 (m, 1 H) 3.81-3.97 (m, 2 H) 3.75 (d, J = 11.98Hz, 1 H) 3.56 (td, isonicotinamide J = 11.71, 2.75 Hz, 1 H) 3.19-3.29(m, 2 H) 2.63-2.80 (m, 1 H) 2.24 (s, 3 H) 2.14 (dd, J = 11.07, 6.66 Hz,1 H) 1.99-2.11 (m, 3 H) 1.59 (d, J = 11.86 Hz, 1 H). LCMS (m/z) (M + H)= 481.3, Rt = 0.96 min. 110

rac-N-(4-methyl- 3-(6-oxo- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- n-9-yl)phenyl)-2- (trifluoromethyl) isonicotinamide¹H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1 H) 9.00 (d, J = 5.01 Hz, 1H) 8.37 (s, 1 H) 8.20 (dd, J = 4.95, 1.04 Hz, 1 H) 8.13 (d, J = 1.59 Hz,1 H) 7.78 (dd, J = 8.25, 2.26 Hz, 1 H) 7.70 (d, J = 2.20 Hz, 1 H) 7.57(d, J = 1.59 Hz, 1 H) 7.39 (d, J = 8.44 Hz, 1 H) 3.85-4.07 (m, 3 H) 3.66(td, J = 11.83, 2.63 Hz, 1 H) 3.48-3.61 (m, 1 H) 3.36-3.45 (m, 1 H) 2.81(td, J = 12.13, 3.73 Hz, 1 H) 2.56-2.65 (m, 2 H) 2.26 (s, 3 H). LCMS(m/z) (M + H) = 483.1, Rt = 1.21 min. 111

rac-N-(3-(6,6- Difluoro- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1 H) 8.99 (d,J = 5.01 Hz, 1 H) 8.36 (s, 1 H) 8.15-8.22 (m, 1 H) 8.06 (d, J = 1.59 Hz,1 H) 7.75 (dd, J = 8.25, 2.26 Hz, 1 H) 7.68 (d, J = 2.20 Hz, 1 H) 7.45(s, 1 H) 7.37 (d, J = 8.44 Hz, 1 H) 3.93-4.03 (m, 2 H) 3.85 (d, J =11.25 Hz, 1 H) 3.60 (td, J = 11.80, 2.69 Hz, 1 H) 3.25-3.42 (m, 2 H)2.79 (td, J = 12.10, 3.42 Hz, 1 H) 2.24 (s, 3 H) 2.11-2.22 (m, 1 H).LCMS (m/z) (M + H) = 505.1, Rt = 1.48 min. 112

rac-N-(4-Methyl- 3-(5-oxo- 1,2,4,4a,5,6- hexahydropyrido[2′,3′:5,6]pyrazino[2, 1-c][1,4]oxazin-9- yl)phenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.13(s, 1 H) 10.68 (s, 1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.20(d, J = 5.22 Hz, 1 H) 7.65- 7.76 (m, 3 H) 7.34 (d, J = 8.44 Hz, 1 H)7.15 (s, 1 H) 4.21 (dd, J = 11.55, 3.73 Hz, 1 H) 3.96 (dd, J = 11.13,3.55 Hz, 1 H) 3.77 (dd, J = 10.27, 3.67 Hz, 1 H) 3.36-3.62 (m, 7 H)3.25-3.29 (m, 2 H) 2.81 (td, J = 12.35, 3.67 Hz, 1 H) 2.38-2.46 (m, 2 H)2.25 (s, 3 H). LCMS (m/z) (M + H) 484.1, Rt. = 1.34 min. 113

rac-N-(3-(6-Ethyl- 5-oxo- 1,2,4,4a,5,6- hexahydropyrido[2′,3′:5,6]pyrazino[2, 1-c][1,4]oxazin-9- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.69(s, 1 H) 8.99 (d, J = 5.01 Hz 1 H) 8.37 (s, 1 H) 8.19 (dd, J = 4.89,1.10 Hz, 1 H) 7.87 (d, J = 1.83 Hz, 1 H) 7.67-7.75 (m, 2 H) 7.35 (d, J =8.07 Hz, 1 H) 7.20 (d, J = 1.71 Hz, 1 H) 4.11-4.29 (m, 2 H) 3.93-4.11(m, 2 H) 3.82 (dd, J = 10.33, 3.85 Hz, 1 H) 3.35-3.63 (m, 3 H) 2.73-2.96(m, 1 H) 2.27 (s, 3 H) 1.18 (t, J = 6.97 Hz, 3 H). LCMS (m/z) (M + H)512.2; Rt = 1.59 min. 114

(S)-N-(3-(6-Ethyl- 5-oxo- 1,2,4,4a,5,6- hexahydropyrido[2′,3′:5,6]pyrazino[2, 1-c][1,4]oxazin-9- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.69(s, 1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.19 (dd, J = 4.89,1.10 Hz, 1 H) 7.87 (d, J = 1.83 Hz, 1 H) 7.67-7.75 (m, 2 H) 7.35 (d, J =8.07 Hz, 1 H) 7.20 (d, J = 1.71 Hz, 1 H) 4.11-4.29 (m, 2 H) 3.93-4.11(m, 2 H) 3.82 (dd, J = 10.33, 3.85 Hz, 1 H) 3.35-3.63 (m, 3 H) 2.73-2.96(m, 1 H) 2.27 (s, 3 H) 1.18 (t, J = 6.97 Hz, 3 H). LCMS (m/z) (M + H)512.2; Rt = 1.59 min. 115

(R)-N-(3-(6-ethyl- 5-oxo- 1,2,4,4a,5,6- hexahydropyrido2′,3′:5,6]pyrazino[2, 1-c][1,4]oxazin-9- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.69(s, 1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.19 (dd, J = 4.89,1.10 Hz, 1 H) 7.87 (d, J = 1.83 Hz, 1 H) 7.67-7.75 (m, 2 H) 7.35 (d, J =8.07 Hz, 1 H) 7.20 (d, J = 1.71 Hz, 1 H) 4.11-4.29 (m, 2 H) 3.93-4.11(m, 2 H) 3.82 (dd, J = 10.33, 3.85 Hz, 1 H) 3.35-3.63 (m, 3 H) 2.73-2.96(m, 1 H) 2.27 (s, 3 H) 1.18 (t, J = 6.97 Hz, 3 H). LCMS (m/z) (M + H)512.2; Rt = 1.59 min.

Example 116rac-trans-2-(1,1-Difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

The title compound was prepared via Suzuki coupling: A vial was chargedwithtrans-2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1 equiv),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.2 equiv), XPhos 2nd Generation Precatalyst (0.05 equiv), potassiumphosphate (3 equiv), and 5:1 1,4-dioxane-water (0.2 M). The vial wassealed and heated to 120° C. for 1 h in the microwave. The mixture wascooled and extracted with EtOAc (3×). The combined organic extracts wereconcentrated. The residue was purified by reverse-phase HPLC (basic) toafford ofrac-trans-2-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide(50% yield) as a white solid after lyophilization. 1H NMR (400 MHz,DMSO-d6) δ ppm 10.62 (s, 1H) 8.87 (d, J=5.11 Hz, 1H) 8.18 (s, 1H) 8.03(d, J=5.11 Hz, 1H) 7.81 (d, J=1.71 Hz, 1H) 7.72 (dd, J=8.25, 2.14 Hz,1H) 7.64 (d, J=2.20 Hz, 1H) 7.32 (d, J=8.44 Hz, 1H) 7.12 (d, J=1.47 Hz,1H) 4.75 (t, J=5.14 Hz, 1H) 4.05 (dd, J=11.25, 2.93 Hz, 1H) 3.88 (dd,J=11.31, 3.12 Hz, 1H) 3.74 (br d, J=11.98 Hz, 1H) 3.34-3.58 (m, 3H)3.24-3.29 (m, 1H) 2.94-3.01 (m, 1H) 2.74-2.87 (m, 3H) 2.23 (s, 3H) 2.05(t, J=19.13 Hz, 3H) 1.86 (td, J=9.14, 5.81 Hz, 1H). LCMS (m/z) (M+H)495.1; Rt=0.98 min.

Examples 117 and 1182-(1,1-Difluoroethyl)-N-(3-((4aR,5R)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideand2-(1,1-difluoroethyl)-N-(3-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

rac-trans-2-(1,1-Difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamidewas subject to chiral SFC. The first eluting enantiomer afforded2-(1,1-difluoroethyl)-N-(3-((4aR,5R)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. The second eluting enantiomer afforded2-(1,1-difluoroethyl)-N-(3-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. NMR and LCMS data for each enantiomer matched that ofthe racemate.

Example 119rac-trans-N-(5-(5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide

The title compound was prepared via Suzuki coupling: ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.66 (s, 1H) 8.86 (d, J=2.45 Hz, 1H) 8.26-8.35 (m, 2H)8.04 (s, 1H) 7.99 (d, J=7.42 Hz, 1H) 7.79-7.87 (m, 2H) 7.20 (d, J=1.71Hz, 1H) 4.76 (t, J=5.20 Hz, 1H) 3.99-4.14 (m, 1H) 3.88 (dd, J=11.25,3.06 Hz, 1H) 3.77 (br d, J=11.98 Hz, 1H) 3.33-3.58 (m, 3H) 3.25-3.30 (m,1H) 3.17 (d, J=5.26 Hz, 1H) 3.00 (ddd, J=10.33, 8.62, 3.18 Hz, 1H)2.75-2.89 (m, 3H) 2.43 (s, 3H) 1.87 (td, J=9.14, 5.69 Hz, 1H). LCMS(m/z) (M+H) 499.1, Rt=0.90 min.

Examples 120 and 121N-(5-((4aR,5R)-5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamideandN-(5-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide

rac-trans-N-(5-(5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamidewas subjected to chiral SFC. The first eluting peak affordedN-(5-((4aR,5R)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamideas a white solid. The second eluting peak affordedN-(5-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamideas a white solid. NMR and LCMS data for each enantiomer matched that ofthe racemate.

Examples 122 and 123rac-trans-N-(3-(5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideandrac-cis-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A vial was charged with(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol(1:1 cis/trans, 1 equiv),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.2 equiv), XPhos 2nd Gen Precatalyst (0.1 equiv), potassium phosphate(3 equiv), and 5:1 1,4-dioxane-water (0.1 M). The vial was sealed andheated to 120° C. for 1 h in the microwave. The mixture was cooled, thenextracted with EtOAc (3×). The combined organic extracts wereconcentrated. The residue was purified by reverse-phase HPLC (basic).Fractions containing product were combined and partially concentrated invacuo, then extracted with DCM (3×). The combined organic extracts weredried over sodium sulfate, filtered, and concentrated to giveN-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1:1 cis/trans, 65.5% yield) as a white solid. This material wassubjected to SFC on a chiral column. The first eluting peak affordedrac-trans-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.67 (s, 1H) 8.99 (d,J=5.01 Hz, 1H) 8.36 (s, 1H) 8.19 (dd, J=4.95, 1.04 Hz, 1H) 7.78-7.84 (m,1H) 7.72 (dd, J=8.31, 2.20 Hz, 1H) 7.64 (d, J=2.08 Hz, 1H) 7.33 (d,J=8.44 Hz, 1H) 7.09-7.21 (m, 1H) 4.63-4.81 (m, 1H) 4.06 (dd, J=11.31,3.00 Hz, 1H) 3.88 (br dd, J=11.43, 3.12 Hz, 1H) 3.81 (br s, 1H) 3.74 (brd, J=12.10 Hz, 1H) 3.49-3.62 (m, 1H) 3.40-3.49 (m, 2H) 3.24-3.29 (m, 1H)2.92-3.03 (m, 1H) 2.74-2.91 (m, 3H) 2.23 (s, 3H) 1.80-1.93 (m, 1H). LCMS(m/z) (M+H)=499.1, Rt=1.00 min. The second eluting peak affordedrac-cis-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.66 (s, 1H) 8.99 (d,J=5.01 Hz, 1H) 8.36 (s, 1H) 8.19 (dd, J=5.01, 1.10 Hz, 1H) 7.82 (d,J=1.59 Hz, 1H) 7.72 (dd, J=8.25, 2.26 Hz, 1H) 7.64 (d, J=2.20 Hz, 1H)7.33 (d, J=8.44 Hz, 1H) 7.18 (d, J=1.71 Hz, 1H) 4.67 (t, J=5.01 Hz, 1H)3.73-3.90 (m, 3H) 3.45-3.64 (m, 3H) 3.33-3.42 (m, 2H) 2.81-2.98 (m, 3H)2.23 (s, 3H) 2.10-2.20 (m, 1H). LCMS (m/z) (M+H)=499.1, Rt=1.00 min.

The following compounds were prepared using methods from the aboveexamples, using appropriate starting materials:

124

rac-2-(1,1- Difluoroethyl)-N- (4-methyl-3-(6- oxo-1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3 - d]pyrido[2,3 - b][1,4]diazepin- 10-yl)phenyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1 H) 10.09 (s, 1 H)8.88 (d, J = 5.10 Hz, 1 H) 8.19 (s, 1 H) 8.01-8.05 (m, 2 H) 7.74 (d, J =7.83 Hz, 1 H) 7.70 (s, 1 H) 7.47 (d, J = 1.96 Hz, 1 H) 7.35 (d, J = 8.31Hz, 1 H) 3.76-3.91 (m, 2 H) 3.37-3.57 (m, 4 H) 2.97 (br d, J = 11.49 Hz,1 H) 2.66- 2.75 (m, 1 H) 2.27 (s, 3 H) 1.98- 2.12 (m, 4 H). LCMS (m/z)(M + H) = isonicotinamide 494.1, Rt = 1.23 min. 125

rac-2-(1,1- Difluoroethyl)-N- (3-(7-ethyl-6- oxo-1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3 - d]pyrido[2,3 - b][1,4]diazepin-10-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.66 (s, 1 H) 8.88 (d, J = 5.07 Hz, 1 H) 8.18 (dd, J = 5.93, 1.28 Hz, 2H) 8.03 (d, J = 5.06 Hz, 1 H) 7.74 (s, 1 H) 7.75 (d, J = 7.58 Hz, 2 H)7.52 (d, J = 2.08 Hz, 1 H) 7.36 (d, J = 9.29 Hz, 1 H) 3.96-4.06 (m, 1 H)3.77-3.89 (m, 3 H) 3.48 (q, J = 10.51 Hz, 2H) 3.23-.29 (m, 1 H) 2.94 (brd, J = 10.51 Hz, 1 H) 2.64-2.71 (m, 1 H) 2.25-2.35 (m, 3 H) 1.98-2.15(m, 4 H) 1.11-1.19 (m, 3 H). LCMS (m/z) (M + H) = 522.2, Rt = 1.41 min.126

(R)-2-(1,1- Difluoroethyl)-N- (3-(7-ethyl-6- oxo-1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3 - d]pyrido[2,3 - b][1,4]diazepin-10-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.66 (s, 1 H) 8.88 (d, J = 5.07 Hz, 1 H) 8.18 (dd, J = 5.93, 1.28 Hz, 2H) 8.03 (d, J = 5.06 Hz, 1 H) 7.74 (s, 1 H) 7.75 (d, J = 7.58 Hz, 2 H)7.52 (d, J = 2.08 Hz, 1 H) 7.36 (d, J = 9.29 Hz, 1 H) 3.96-4.06 (m, 1 H)3.77-3.89 (m, 3 H) 3.48 (q, J = 10.51 Hz, 2H) 3.23-3.29 (m, 1 H) 2.94(br d, J = 10.51 Hz, 1 H) 2.64-2.71 (m, 1 H) 2.25-2.35 (m, 3 H)1.98-2.15 (m, 4 H) 1.11-1.19 (m, 3 H). LCMS (m/z) (M + H) = 522.2, Rt =1.41 min. 127

(S)-2-(1,1- difluoroethyl)-N- (3-(7-ethyl-6- oxo-1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3 - d]pyrido[2,3 - b][1,4]diazepin-10-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.66 (s, 1 H) 8.88 (d, J = 5.07 Hz, 1 H) 8.18 (dd, J = 5.93, 1.28 Hz, 2H) 8.03 (d, J = 5.06 Hz, 1 H) 7.74 (s, 1 H) 7.75 (d, J = 7.58 Hz, 2 H)7.52 (d, J = 2.08 Hz, 1 H) 7.36 (d, J = 9.29 Hz, 1 H) 3.96-4.06 (m, 1 H)3.77-3.89 (m, 3 H) 3.48 (q, J = 10.51 Hz, 2H) 3.23-3.29 (m, 1 H) 2.94(br d, J = 10.51 Hz, 1 H) 2.64-2.71 (m, 1 H) 2.25-2.35 (m, 3 H)1.98-2.15 (m, 4 H) 1.11-1.19 (m, 3 H). LCMS (m/z) (M + H) = 522.2, Rt =1.41 min. 128

rac-N-(3-(7- Ethyl-6-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3 -d]pyrido[2,3 - b][1,4]diazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70(s, 1 H) 9.00 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.18-8.21 (m, 1 H)8.18 (s, 1 H) 7.73 (s, 1 H) 7.74 (d, J = 7.26 Hz, 2 H) 7.52 (d, J = 2.08Hz, 1 H) 7.37 (d, J = 9.05 Hz, 1 H) 3.96-4.06 (m, 1 H) 3.77-3.90 (m, 3H) 3.39-3.57 (m, 3 H) 2.94 (br d, J = 11.37 Hz, 1 H) 2.54-2.71 (m, 1 H)2.28 (s, 3 H) 2.12 (d, J = 13.45 Hz, 1 H) 1.08-1.25 (m, 3 H). LCMS (m/z)(M + H) = 526.2, Rt = 1.45 min. 129

(R)-N-(3-(7- Ethyl-6-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-d]pyrido[2,3 - b][1,4]diazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70(s, 1 H) 9.00 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.18-8.21 (m, 1 H)8.18 (s, 1 H) 7.73 (s, 1 H) 7.74 (d, J = 7.26 Hz, 2 H) 7.52 (d, J = 2.08Hz, 1 H) 7.37 (d, J = 9.05 Hz, 1 H) 3.96-4.06 (m, 1 H) 3.77-3.90 (m, 3H) 3.39-3.57 (m, 3 H) 2.94 (br d, J = 11.37 Hz, 1 H) 2.54-2.71 (m, 1 H)2.28 (s, 3 H) 2.12 (d, J = 13.45 Hz, 1 H) 1.08-1.25 (m, 3 H). LCMS (m/z)(M + H) = 526.2, Rt = 1.45 min. 130

(S)-N-(3-(7-ethyl- 6-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-d]pyrido[2,3- b][1,4]diazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70(s, 1 H) 9.00 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.18-8.21 (m, 1 H)8.18 (s, 1 H) 7.73 (s, 1 H) 7.74 (d, J = 7.26 Hz, 2 H) 7.52 (d, J = 2.08Hz, 1 H) 7.37 (d, J = 9.05 Hz, 1 H) 3.96-4.06 (m, 1 H) 3.77-3.90 (m, 3H) 3.39-3.57 (m, 3 H) 2.94 (br d, J = 11.37 Hz, 1 H) 2.54-2.71 (m, 1 H)2.28 (s, 3 H) 2.12 (d, J = 13.45 Hz, 1 H) 1.08-1.25 (m, 3 H). LCMS (m/z)(M + H) = 526.2, Rt = 1.45 min. 131

rac-N-(5-(7- Ethyl-6-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-d]pyrido[2,3- b][1,4]diazepin- 10-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1H) 8.87 (d, J = 2.45 Hz, 1 H) 8.22-8.36 (m, 2 H) 8.14 (d, J = 2.45 Hz, 1H) 8.00 (d, J = 7.82 Hz, 1 H) 7.79-7.85 (m, 1 H) 7.61 (d, J = 2.08 Hz, 1H) 4.02 (br dd, J = 13.33, 6.85 Hz, 1 H) 3.66-3.91 (m, 3 H) 3.35-3.62(m, 3 H) 2.90- 3.02 (m, 1 H) 2.63-2.82 (m, 2 H) 2.13 (d, J = 13.57 Hz, 1H) 1.16 (t, J = 7.03 Hz, 3 H). LCMS (m/z) (M + H) = 526.5, Rt = 1.10min. 132

rac-N-(3-(5- Ethyl-6-oxo- 5,6,6a,7,9,10- hexahydropyridazino[3′,4′:5,6]pyrazino [2,1-c][1,4]oxazin-2- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.73(s, 1 H) 9.00 (d, J = 4.89 Hz, 1 H) 8.38 (s, 1 H) 8.20 (dd, J = 5.01,1.10 Hz, 1 H) 7.85 (d, J = 2.20 Hz, 1 H) 7.78 (dd, J = 8.25, 2.26 Hz, 1H) 7.37 (d, J = 8.44 Hz, 1 H) 7.04 (s, 1 H) 4.12-4.30 (m, 4 H) 3.93-4.06(m, 1 H) 3.77 (br d, J = 11.00 Hz, 1 H) 3.52-3.61 (m, 2 H) 2.89-2.99 (m,1 H) 2.32 (s, 3 H) 1.15-1.32 (m, 6 H). LCMS (m/z) (M + H) = 512.2, Rt =1.02 min. 133

(S)-N-(3-(5- Ethyl-6-oxo- 5,6,6a,7,9,10- hexahydropyridazino [3′,4′:5,6]pyrazino[2,1- c][1,4]oxazin-2- yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.73 (s, 1 H) 9.00 (d,J = 4.89 Hz, 1 H) 8.38 (s, 1 H) 8.20 (dd, J = 5.01, 1.10 Hz, 1 H) 7.85(d, J = 2.20 Hz, 1 H) 7.78 (dd, J = 8.25, 2.26 Hz, 1 H) 7.37 (d, J =8.44 Hz, 1 H) 7.04 (s, 1 H) 4.12-4.30 (m, 4 H) 3.93-4.06 (m, 1 H) 3.77(br d, J = 11.00 Hz, 1 H) 3.52-3.61 (m, 2 H) 2.89-2.99 (m, 1 H) 2.32 (s,3 H) 1.15-1.32 (m, 6 H). LCMS (m/z) (M + H) = 512.2, Rt = 1.02 min. 134

(R)-N-(3-(5- ethyl-6-oxo- 5,6,6a,7,9,10- hexahydropyridazino [3′,4′:5,6]pyrazino[2,1- c][1,4]oxazin-2- yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.73 (s, 1 H) 9.00 (d,J = 4.89 Hz, 1 H) 8.38 (s, 1 H) 8.20 (dd, J = 5.01, 1.10 Hz, 1 H) 7.85(d, J = 2.20 Hz, 1 H) 7.78 (dd, J = 8.25, 2.26 Hz, 1 H) 7.37 (d, J =8.44 Hz, 1 H) 7.04 (s, 1 H) 4.12-4.30 (m, 4 H) 3.93-4.06 (m, 1 H) 3.77(br d, J = 11.00 Hz, 1 H) 3.52-3.61 (m, 2 H) 2.89-2.99 (m, 1 H) 2.32 (s,3 H) 1.15-1.32 (m, 6 H). LCMS (m/z) (M + H) = 512.2, Rt = 1.02 min. 135

rac-2-(1,1- Difluoroethyl)-N- (4-methyl-3- (6a,7,9,10- tetrahydro-6H-[1,4]oxazino[4,3- d]pyridazino[3,4- b][1,4]oxazin-2- yl)phenyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.67 (s, 1 H) 8.88 (d,J = 5.01 Hz, 1 H) 8.19 (s, 1 H) 8.04 (d, J = 5.19 Hz, 1 H) 7.78 (s, 1 H)7.77 (d, J = 7.29 Hz, 2 H) 7.33 (d, J = 9.17 Hz, 1H) 7.04 (s, 1 H) 4.51(dd, J = 11.13, 3.18 Hz, 1 H) 4.10 (dd, J = 11.13, 9.17 Hz, 1 H) 3.96(ddd, J = 14.82, 11.46, 3.42 Hz, 2 H) 3.82 (br d, J = 11.13 Hz, 1 H)3.36-3.59 (m, 2 H) 3.12-3.27 (m, 1 H) 2.89-3.02 (m, 1 H) 2.28 (s, 3 H)2.05 (t, J = 19.13 Hz, 3 H). LCMS (m/z) (M + H) = 468.5, Rt = 0.91 min.136

rac-2-(1,1- Difluoroethyl)-N- (3-(6,6-dimethyl- 6a,7,9,10-tetrahydro-6H- [1,4]oxazino[4,3- d]pyridazino[3,4- b][1,4]oxazin-2-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.65 (s, 1 H) 8.88 (d, J = 5.12 Hz, 1 H) 8.18-8.21 (m, 1 H) 8.04 (d, J= 5.16 Hz, 1 H) 7.79 (s, 1 H) 7.78 (d, J = 9.58 Hz, 1 H) 7.33 (d, J =7.95 Hz, 1 H) 7.07 (s, 1 H) 3.93-4.08 (m, 2 H) 3.87 (dd, J = 12.59, 1.83Hz, 1 H) 3.57 (td, J = 11.92, 2.81 Hz, 1 H) 3.33- 3.41 (m, 1 H)3.24-3.30 (m, 1 H) 2.95 (td, J = 12.38, 3.97 Hz, 1 H) 2.29 (s, 3 H)1.98-2.12 (m, 3 H) 1.43 (s, 3 H) 1.28 (s, 3 H). LCMS (m/z) (M + H) =496.1, Rt = 1.01 min. 137

(S)-2-(1,1- Difluoroethyl)-N- (3-(6,6-dimethyl- 6a,7,9,10-tetrahydro-6H- [1,4]oxazino[4,3 - d]pyridazino[3,4- b][1,4]oxazin-2-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm10.65 (s, 1 H) 8.88 (d, J = 5.12 Hz, 1 H) 8.18-8.21 (m, 1 H) 8.04 (d, J= 5.16 Hz, 1 H) 7.79 (s, 1 H) 7.78 (d, J = 9.58 Hz, 1 H) 7.33 (d, J =7.95 Hz, 1 H) 7.07 (s, 1 H) 3.93-4.08 (m, 2 H) 3.87 (dd, J = 12.59, 1.83Hz, 1 H) 3.57 (td, J = 11.92, 2.81 Hz, 1 H) 3.33- 3.41 (m, 1 H)3.24-3.30 (m, 1 H) 2.95 (td, J = 12.38, 3.97 Hz, 1 H) 2.29 (s, 3 H)1.98-2.12 (m, 3 H) 1.43 (s, 3 H) 1.28 (s, 3 H). LCMS (m/z) (M + H) =496.1, Rt = 1.01 min. 138

(R)-2-(1,1- Difluoroethyl)-N- (3-(6,6-dimethyl- 6a,7,9,10-tetrahydro-6H- [1,4]oxazino[4,3- d]pyridazino[3,4- b][1,4]oxazin-2-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.65 (s, 1 H) 8.88 (d, J = 5.12 Hz, 1 H) 8.18-8.21 (m, 1 H) 8.04 (d, J= 5.16 Hz, 1 H) 7.79 (s, 1 H) 7.78 (d, J = 9.58 Hz, 1 H) 7.33 (d, J =7.95 Hz, 1 H) 7.07 (s, 1 H) 3.93-4.08 (m, 2 H) 3.87 (dd, J = 12.59, 1.83Hz, 1 H) 3.57 (td, J = 11.92, 2.81 Hz, 1 H) 3.33- 3.41 (m, 1 H)3.24-3.30 (m, 1 H) 2.95 (td, J = 12.38, 3.97 Hz, 1 H) 2.29 (s, 3 H)1.98-2.12 (m, 3 H) 1.43 (s, 3 H) 1.28 (s, 3 H). LCMS (m/z) (M + H) =496.1, Rt = 1.01 min. 139

rac-N-(3-(6,6- dimethyl- 6a,7,9,10- tetrahydro-6H- [1,4]oxazino[4,3-d]pyridazino[3,4- b][1,4]oxazin-2- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70(s, 1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.38 (s, 1 H) 8.20 (d, J = 5.12 Hz,1 H) 7.78 (d, J = 9.24 Hz, 2 H) 7.34 (d, J = 7.95 Hz, 1 H) 7.07 (s, 1 H)3.92-4.08 (m, 2 H) 3.85-3.92 (m, 1 H) 3.57 (td, J = 11.89, 2.75 Hz, 2 H)3.24-3.30 (m, 1 H) 2.95 (td, J = 12.32, 3.85 Hz, 1 H) 2.29 (s, 3 H) 1.43(s, 3 H) 1.28 (s, 3 H). LCMS (m/z) (M + H) = 500.1, Rt = 1.03 min. 140

rac-2-(1,1- difluoroethyl)-N- (3-((4aS*,5S*,6S*)- 5-fluoro-6- hydroxy-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1 H) 8.77-8.99(m, 1 H) 8.13-8.23 (m, 1 H) 8.02 (s, 2 H) 7.61-7.80 (m, 2 H) 7.30-7.41(m, 1 H) 7.13-7.26 (m, 1 H) 5.79-5.94 (m, 1 H) 4.77-4.92 (m, 1 H) 4.53-4.73 (m, 1 H) 3.91-4.16 (m, 3 H) 3.71-3.84 (m, 1 H) 3.48-3.63 (m, 3 H)2.65-2.88 (m, 1 H) 2.23 (s, 3 H) 1.92-2.16 (m, 4 H). LCMS (m/z) (M + H)= 499.5, Rt = 1.03 min. isonicotinamide 141

rac-cis-2-(2- fluoropropan-2- yl)-N-(3-(6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 8.75 (d,J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.82 (dd, J = 4.8, 0.8 Hz,1H), 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 8.3 Hz,1H), 7.17 (s, 1H), 5.23 (d, J = 2.3 Hz, 1H), 4.77 (m, 1H), 3.91 (m, 1H),3.85 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 11.7 Hz, 1H), 3.57 (m, 1H), 3.26(m, 2H), 2.72 (td, J = 12.0, 3.3 Hz, 1H), 2.24 (s, 3H), 2.15 (dd, J =11.6, 6.5 Hz, 1H), 1.71 (d, J = 22.1 Hz, 6H), 1.59 (m, 1H). LCMS (m/z)(M + H) = 477.5, Rt = 0.97 min. 142

2-(2- fluoropropan-2- yl)-N-(3- ((4aR,6R)-6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H),8.02 (s, 1H), 7.91 (s, 1H), 7.82 (dd, J = 4.8, 0.8 Hz, 1H), 7.73 (dd, J= 8.0, 1.6 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.17 (s,1H), 5.23 (d, J = 2.3 Hz, 1H), 4.77 (m, 1H), 3.91 (m, 1H), 3.85 (d, J =8.0 Hz, 1H), 3.75 (d, J = 11.7 Hz, 1H), 3.57 (m, 1H), 3.26 (m, 2H), 2.72(td, J = 12.0, 3.3 Hz, 1H), 2.24 isonicotinamide (s, 3H), 2.15 (dd, J =11.6, 6.5 Hz, 1H), 1.71 (d, J = 22.1 Hz, 6H), 1.59 (m, 1H). LCMS (m/z)(M + H) = 477.5, Rt = 0.97 min. 143

2-(2- fluoropropan-2- yl)-N-(3- ((4aS,6S)-6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3 a][1,5]naphthyridin 9-yl)-4- methylphenyl)¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H),8.02 (s, 1H), 7.91 (s, 1H), 7.82 (dd, J = 4.8, 0.8 Hz, 1H), 7.73 (dd, J= 8.0, 1.6 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.17 (s,1H), 5.23 (d, J = 2.3 Hz, 1H), 4.77 (m, 1H), 3.91 (m, 1H), 3.85 (d, J =8.0 Hz, 1H), 3.75 (d, J = 11.7 Hz, 1H), 3.57 (m, 1H), 3.26 (m, 2H), 2.72(td, J = 12.0, 3.3 Hz, 1H), 2.24 isonicotinamide (s, 3H), 2.15 (dd, J =11.6, 6.5 Hz, 1H), 1.71 (d, J = 22.1 Hz, 6H), 1.59 (m, 1H). LCMS (m/z)(M + H) = 477.5, Rt = 0.97 min. 144

rac-cis-N-(3-(6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-5- (trifluoromethyl)nicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 9.30 (s,1H), 9.11 (s, 1H), 8.61 (s, 1H), 7.84 (s, 1H), 7.66 (d, J = 7.3 Hz, 1H),7.58 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 5.16 (s, 1H), 4.70(br s, 1H), 3.81 (dd, J = 26.2, 8.8 Hz, 2H), 3.68 (d, J = 11 Hz, 1H),3.49 (m, 2H), 2.65 (m, 1H), 2.17 (s, 3H), 2.08 (d, J = 6.9 Hz, 1H), 1.52(d, J = 11.4 Hz, 1H). Signal for one aliphatic proton is hidden bysolvent peak. LCMS (m/z) (M + H) = 485.1, Rt = 1.00 min. 145

N-(3-((4aR,6R)- 6-hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-5- (trifluoromethyl)nicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 9.30 (s,1H), 9.11 (s, 1H), 8.61 (s, 1H), 7.84 (s, 1H), 7.66 (d, J = 7.3 Hz, 1H),7.58 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 5.16 (s, 1H), 4.70(br s, 1H), 3.81 (dd, J = 26.2, 8.8 Hz, 2H), 3.68 (d, J = 11 Hz, 1H),3.49 (m, 2H), 2.65 (m, 1H), 2.17 (s, 3H), 2.08 (d, J = 6.9 Hz, 1H), 1.52(d, J = 11.4 Hz, 1H). Signal for one aliphatic proton is hidden bysolvent peak. LCMS (m/z) (M + H) = 485.1, Rt = 1.00 min. 146

N-(3-((4aS,6S)-6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-5- (trifluoromethyl)nicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 9.30 (s,1H), 9.11 (s, 1H), 8.61 (s, 1H), 7.84 (s, 1H), 7.66 (d, J = 7.3 Hz, 1H),7.58 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 5.16 (s, 1H), 4.70(br s, 1H), 3.81 (dd, J = 26.2, 8.8 Hz, 2H), 3.68 (d, J = 11 Hz, 1H),3.49 (m, 2H), 2.65 (m, 1H), 2.17 (s, 3H), 2.08 (d, J = 6.9 Hz, 1H), 1.52(d, J = 11.4 Hz, 1H). Signal for one aliphatic proton is hidden bysolvent peak. LCMS (m/z) (M + H) = 485.1, Rt = 1.00 min. 147

rac-cis-N-(3-(6- hydroxy- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-4- (trifluoromethyl)picolinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.79 (br s, 1H), 9.03 (d,J = 5.0 Hz, 1H), 8.34 (s, 1H), 8.10 (d, J = 4.6 Hz, 1H), 7.93 (s, 1H),7.87 (dd, J = 8.2, 2.0 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.32 (d, J =8.3 Hz, 1H), 7.18 (s, 1H), 5.23 (s, 1H), 4.77 (m, 1H), 3.92 (d, J = 9.0Hz, 1H), 3.85 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 11.7 Hz, 1H), 3.57 (t, J= 10.5 Hz, 1H), 2.72 (td, J = 12.0, 3.3 Hz, 1H), 2.25 (s, 3H), 2.15 (dd,J = 11.6, 6.5 Hz, 1H), 1.60 (m, 1H). LCMS (m/z) (M + H) = 485.4, Rt =1.06 min. 148

rac-cis-2-(1,1- difluoroethyl)-N- (5-(6-hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-6-methylpyridin-3- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.78 (s, 1H), 8.84 (d, J = 4.6 Hz, 1H), 8.80 (s, 1H), 8.14 (s, 1H),7.98 (s, 2H), 7.89 (s, 1H), 7.18 (s, 1H), 5.20 (d, J = 2.9 Hz, 1H), 4.70(br s, 1H), 3.85 (d, J = 10.4 Hz, 1H), 3.79 (d, J = 7.3 Hz, 1H), 3.70(d, J = 12.0 Hz, 1H), 3.49 (t, J = 10.8 Hz, 1H), 3.21 (m, 1H), 2.66 (t,J = 10.6 Hz, 1H), 2.37 (s, 3H), 2.08 (m, 2H), 1.99 (t, J = 19.1 Hz, 3H),1.53 (q, J = 10.4, 9.7 Hz, 1H). LCMS (m/z) (M + H) = 482.3, Rt = 0.80min. 149

rac-cis-2-(2- cyanopropan-2- yl)-N-(3-(6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 8.81 (d,J = 5.0 Hz, 1H), 8.00 (s, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.86 (dd, J =5.0, 1.2 Hz, 1H), 7.71 (dd, J = 8.2, 2.0 Hz, 1H), 7.64 (d, J = 1.9 Hz,1H), 7.33 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.23 (d, J =3.5 Hz, 1H), 4.77 (m, 1H), 3.92 (dd, J = 11.3, 2.6 Hz, 1H), 3.85 (d, J =8.0 Hz, 1H), 3.75 (d, J = 11.7 Hz, 1H), 3.56 (td, J = 11.6, 2.4 Hz, 1H),3.25 (m, 2H), 2.71 (td, J = 12.0, 3.4 Hz, 1H), 2.24 (s, 3H), 1.77 (s,6H), 1.59 (m, 1H). LCMS (m/z) (M + H) = 484.5, Rt = 0.95 min. 150

2-(2- cyanopropan-2- yl)-N-(3- ((4aR,6R)-6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 8.81 (d, J = 5.0 Hz, 1H),8.00 (s, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 5.0, 1.2 Hz, 1H),7.71 (dd, J = 8.2, 2.0 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.33 (d, J =8.4 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.23 (d, J = 3.5 Hz, 1H), 4.77(m, 1H), 3.92 (dd, J = 11.3, 2.6 Hz, 1H), 3.85 (d, J = 8.0 Hz, 1H), 3.75(d, J = 11.7 Hz, 1H), 3.56 (td, J = 11.6, 2.4 isonicotinamide Hz, 1H),3.25 (m, 2H), 2.71 (td, J = 12.0, 3.4 Hz, 1H), 2.24 (s, 3H), 1.77 (s,6H), 1.59 (m, 1H). LCMS (m/z) (M + H) = 484.5, Rt = 0.95 min. 151

2-(2- cyanopropan-2- yl)-N-(3- ((4aS,6S)-6- hydroxy- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 8.81 (d, J = 5.0 Hz, 1H),8.00 (s, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 5.0, 1.2 Hz, 1H),7.71 (dd, J = 8.2, 2.0 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.33 (d, J =8.4 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.23 (d, J = 3.5 Hz, 1H), 4.77(m, 1H), 3.92 (dd, J = 11.3, 2.6 Hz, 1H), 3.85 (d, J = 8.0 Hz, 1H), 3.75(d, J = 11.7 Hz, 1H), 3.56 (td, J = 11.6, 2.4 isonicotinamide Hz, 1H),3.25 (m, 2H), 2.71 (td, J = 12.0, 3.4 Hz, 1H), 2.24 (s, 3H), 1.77 (s,6H), 1.59 (m, 1H). LCMS (m/z) (M + H) = 484.5, Rt = 0.95 min. 152

rac-2-(1,1- difluoroethyl)-N- (4-methyl-3- (2,4,4a,6- tetrahydro-1H-spiro[[1,4]oxazino [4,3-a] [1,5]naphthyridine- 5,3′-oxetan]- ¹H NMR (400MHz DMSO-d₆) δ ppm 10.61 (s, 1H), 8.88 (d, J = 5.0 Hz, 1H), 8.18 (s,1H), 8.02 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.72 (dd, J =8.2, 2.0 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H),7.20 (d, J = 1.2 Hz, 1H), 4.57 (dd, J = 20.1, 6.3 Hz, 2H), 4.33 (dd, J =13.9, 6.3 Hz, 2H), 4.22 (dd, J = 9-yl)phenyl) 11.2, 2.7 Hz, 1H), 3.86(d, J = 11.1 isonicotinamide Hz, 2H), 3.69 (t, J = 11.0 Hz, 1H), 3.57(t, J = 10.6 Hz, 1H), 3.43 (dd, J = 10.7, 2.9 Hz, 1H), 3.21 (s, 2H),2.93 (td, J = 12.6, 3.4 Hz, 1H), 2.22 (s, 3H), 2.05 (t, J = 19.1 Hz,3H). LCMS (m/z) (M + H) = 507.5, Rt = 0.98 min. 153

rac-2-(1,1- difluoroethyl)-N- (4-methyl-3- (2,4,4a,6- tetrahydro-1H-spiro[[1,4]oxazino [4,3-a] [1,5]naphthyridine- 5,3′-oxetan]- 1H NMR (400MHz, DMSO-d₆) δ ppm 10.78 (s, 1H), 9.00 (d, J = 4.9 Hz, 1H), 8.36 (s,1H), 8.19 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H),7.72 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H), 4.61 (d, J = 6.5 Hz, 2H), 4.55(d, J = 6.5 Hz, 2H), 4.39 (dd, J = 6.4, 2.3 Hz, 2H), 4.20 (d, J = 9.1Hz, 1H), 4.04 (d, J = 12.6 Hz, 1H) 3.88 9-yl)phenyl) (d, J = 11.1 Hz,1H), 3.67 (m, 2H), isonicotinamide 3.57 (m, 1H), 3.08 (td, J = 12.6, 3.1Hz, 1H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 511.3, Rt = 1.00 min. 154

(R)-N-(4-methyl- 3-(1′,2′,4′,4a′- tetrahydro-6′H- spiro[oxetane-3,5′-[1,4]oxazino[4,3- a][1,5]naphthyridin]- 9′-yl)phenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.78 (s, 1H), 9.00 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 4.8Hz, 1H), 8.13 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.72 (m, 2H), 7.39 (d,J = 8.3 Hz, 1H), 4.61 (d, J = 6.5 Hz, 2H), 4.55 (d, J = 6.5 Hz, 2H),4.39 (dd, J = 6.4, 2.3 Hz, 2H), 4.20 (d, J = 9.1 Hz, 1H), 4.04 (d, J =12.6 Hz, 1H) 3.88 (d, J = 11.1 Hz, 1H), 3.67 (m, 2H), 3.57 (m, 1H), 3.08(td, J = 12.6, 3.1 Hz, 1H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 511.3, Rt= 1.00 min. 155

(S)-N-(4-methyl- 3-(1′,2′,4′,4a′- tetrahydro-6′H- spiro[oxetane- 3,5′-[1,4]oxazino[4,3- a][1,5]naphthyridin]- 9′-yl)phenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.78 (s, 1H), 9.00(d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 4.8 Hz, 1H), 8.13 (s,1H), 7.76 (d, J = 1.7 Hz, 1H), 7.72 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H),4.61 (d, J = 6.5 Hz, 2H), 4.55 (d, J = 6.5 Hz, 2H), 4.39 (dd, J = 6.4,2.3 Hz, 2H), 4.20 (d, J = 9.1 Hz, 1H), 4.04 (d, J = 12.6 Hz, 1H) 3.88isonicotinamide (d, J = 11.1 Hz, 1H), 3.67 (m, 2H), 3.57 (m, 1H), 3.08(td, J = 12.6, 3.1 Hz, 1H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 511.3, Rt= 1.00 min. 156

rac-N-(6-methyl- 5-(2,4,4a,6- tetrahydro-1H- spiro[[1,4]oxazino [4,3-a][1,5]naphthyridine- 5,3′-oxetan]- 9-yl)pyridin-3- yl)-3- ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.32 (s,1H), 8.28 (d, J = 8.0 Hz, 1H) 8.03 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 7.8Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.28 (d, J= 1.7 Hz, 1H), 4.59 (d, J = 6.3 Hz, 1H), 4.54 (d, J = 6.3 Hz, 1H), 4.34(d, J = 6.4 Hz, 1H), 4.31 (d, J = (trifluoromethyl) 6.3 Hz, 1H), 4.22(dd, J = 11.3, 3.0 benzamide Hz, 1H), 3.89 (d, J = 4.4 Hz, 1H), 3.86 (d,J = 3.8 Hz, 1H), 3.68 (t, J = 11.0 Hz, 1H), 3.57 (td, J = 11.8, 2.5 Hz,1H), 3.45 (dd, J = 10.7, 3.1 Hz, 1H), 3.21 (s, 2H), 2.94 (m, 1H), 2.42(s, 3H). LCMS (m/z) (M + H) = 511.4, Rt = 0.91 min. 157

rac-2-(2- cyanopropan-2- yl)-N-(4-methyl- 3-(2,4,4a,6- tetrahydro-1H-spiro[[1,4]oxazino [4,3-a] [1,5]naphthyridine- 5,3′-oxetan]- ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.52 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 7.99 (s,1H), 7.85 (m, 2H), 7.70 (dd, J = 8.2, 2.2 Hz, 1H), 7.62 (d, J = 2.1 Hz,1H), 7.32 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 4.59 (d, J =6.2 Hz, 1H), 4.54 (d, J = 6.3 Hz, 1H), 4.34 (d, J = 6.4 Hz, 1H), 4.30(d, J = 6.3 Hz, 1H), 4.21 (m, 9-yl)phenyl) 1H), 3.87 (s, 1H), 3.85 (s,1H), 3.68 isonicotinamide (t, J = 11.0 Hz, 1H), 3.57 (td, J = 11.8, 2.5Hz, 1H), 3.43 (dd, J = 10.5, 2.9 Hz, 1H), 3.20 (s, 2H), 2.92 (m, 1H),2.22 (s, 3H), 1.76 (s, 6H). LCMS (m/z) (M + H) = 510.5, Rt = 0.96 min.158

rac-N-(3-(5,5- bis(hydroxymethyl)- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.55 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.11 (s, 1H), 7.96 (d, J = 4.5Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 6.5 Hz, 1H), 7.58 (s, 1H), 7.25 (d,J = 8.3 Hz, 1H), 7.12 (s, 1H), 4.63 (s, 1H), 4.51 (s, 1H), 3.91 (d, J =8.8 Hz, 1H), 3.83 (d, J = 12.4 Hz, 1H), 3.71 (d, J = 9.3 Hz, 1H), 2.83(t, J = 10.9 Hz, 1H), 2.67 (m, 2H), 3.36 (m, 6H), 2.17 (s, 3H), 1.98 (t,J = 19.1 Hz, 3H). Signal for one aliphatic proton is hidden undersolvent peak. LCMS (m/z) (M + H) = 525.4, Rt = 0.93 min. 159

rac-N-(3-(5,5- bis(hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-4-(trifluoromethyl) picolinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.86 (s,1H), 9.04 (d, J = 5.0 Hz, 1H), 8.34 (s, 1H), 8.11 (d, J = 3.6 Hz, 2H),7.91 (m, 2H), 7.78 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 4.11 (d, J = 12.8Hz, 1H), 4.02 (d, J = 8.9 Hz, 1H), 3.82 (m, 1H), 3.47 (m, 8H), 3.09 (m,2H), 2.92 (m, 2H), 2.27 (s, 3H). Eight aliphatic proton signals appearto overlap with water peak. LCMS (m/z) (M + H) = 529.4, Rt = 1.02 min.160

rac-cis-2-(1,1- difluoroethyl)-N- (3-(6-hydroxy- 5,5-dimethyl-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H), 8.88 (d, J= 5.0 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 1.5Hz, 1H), 7.74 (dd, J =+) 8.3, 2.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H),7.33 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 5.04 (s, 1H), 4.33(s, 1H), 3.97 (dd, J = 11.2, 2.9 Hz, 1H), 3.88 (dd, J = 11.5, 2.4 Hz,2H), 3.50 (q, J = 10.8, isonicotinamide 9.9 Hz, 2H), 3.08 (dd, J = 10.6,3.1 Hz, 1H), 2.85 (td, J = 12.3, 3.6 Hz, 1H), 2.24 (s, 3H), 2.05 (t, J =19.1 Hz, 3H), 1.08 (s, 3H), 0.81 (s, 3H). LCMS (m/z) (M + H) = 509.5, Rt= 1.03 min. 161

2-(1,1- difluoroethyl)-N- (3-((4aR,6R)-6- hydroxy-5,5- dimethyl-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H), 8.88 (d, J = 5.0 Hz, 1H),8.18 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.74(dd, J = 8.3, 2.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 8.4Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 5.04 (s, 1H), 4.33 (s, 1H), 3.97 (dd,J = 11.2, 2.9 Hz, 1H), 3.88 (dd, J = 11.5, 2.4 Hz, 2H), 3.50 (q, J =10.8, methylphenyl) 9.9 Hz, 2H), 3.08 (dd, J = 10.6, 3.1 isonicotinamideHz, 1H), 2.85 (td, J = 12.3, 3.6 Hz, 1H), 2.24 (s, 3H), 2.05 (t, J =19.1 Hz, 3H), 1.08 (s, 3H), 0.81 (s, 3H). LCMS (m/z) (M + H) = 509.5, Rt= 1.03 min. 162

N-(3-((4aR,6R)- 5,5-difluoro-6- hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H), 8.88(d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.90 (d, J= 1.5 Hz, 1H), 7.74 (dd, J = 8.3, 2.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H),7.33 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 5.04 (s, 1H), 4.33(s, 1H), 3.97 (dd, J = 11.2, 2.9 Hz, 1H), 3.88 (dd, J = 11.5, 2.4 Hz,2H), 3.50 (q, J = 10.8,. isonicotinamide 9.9 Hz, 2H), 3.08 (dd, J =10.6, 3.1 Hz, 1H), 2.85 (td, J = 12.3, 3.6 Hz, 1H), 2.24 (s, 3H), 2.05(t, J = 19.1 Hz, 3H), 1.08 (s, 3H), 0.81 (s, 3H). LCMS (m/z) (M + H) =509.5, Rt = 1.03 min. 163

rac-cis-N-(3-(5,5- difluoro-6- hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 8.88(d, J = 5.1 Hz, 1H), 8.17 (s, 1H), 8.03 (m, 2H), 7.74 (dd, J = 8.3, 2.1Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.31 (d, J= 1.4 Hz, 1H), 6.17 (br s, 1H), 4.99 (m, 1H), 4.09 (d, J = 8.0 Hz, 1H),3.94 (d, J = 8.7 Hz, 1H), 3.88 (d, J = 11.8 Hz, 1H), 3.79 (m, 1H), 3.68(t, J = 10.7 Hz, 1H), isonicotinamide 3.58 (m, 1H), 2.86 (m, 1H), 2.24(s, 3H), 2.05 (t, J = 19.1 Hz, 3H). LCMS (m/z) (M + H) = 517.4, Rt =1.10 min. 164

N-(3-((4aS,6S)- 5,5-difluoro-6- hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 8.88(d, J = 5.1 Hz, 1H), 8.17 (s, 1H), 8.03 (m, 2H), 7.74 (dd, J = 8.3, 2.1Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.31 (d, J= 1.4 Hz, 1H), 6.17 (br s, 1H), 4.99 (m, 1H), 4.09 (d, J = 8.0 Hz, 1H),3.94 (d, J = 8.7 Hz, 1H), 3.88 (d, J = 11.8 Hz, 1H), 3.79 (m, 1H), 3.68(t, J = 10.7 Hz, 1H), isonicotinamide 3.58 (m, 1H), 2.86 (m, 1H), 2.24(s, 3H), 2.05 (t, J = 19.1 Hz, 3H). LCMS (m/z) (M + H) = 517.4, Rt =1.10 min. 165

N-(3-((4aR,6R)- 5,5-difluoro-6- hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 8.88(d, J = 5.1 Hz, 1H), 8.17 (s, 1H), 8.03 (m, 2H), 7.74 (dd, J = 8.3, 2.1Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.31 (d, J= 1.4 Hz, 1H), 6.17 (br s, 1H), 4.99 (m, 1H), 4.09 (d, J = 8.0 Hz, 1H),3.94 (d, J = 8.7 Hz, 1H), 3.88 (d, J = 11.8 Hz, 1H), 3.79 (m, 1H), 3.68(t, J = 10.7 Hz, 1H), isonicotinamide 3.58 (m, 1H), 2.86 (m, 1H), 2.24(s, 3H), 2.05 (t, J = 19.1 Hz, 3H). LCMS (m/z) (M + H) = 517.4, Rt =1.10 min. 166

rac-cis-N-(3-(5,5- difluoro-6- hydroxy- 1′2′4′4a′5′6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1H), 8.99(d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 4.8 Hz, 1H), 8.04 (d, J= 1.4 Hz, 1H), 7.73 (dd, J = 8.3, 2.1 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H),7.36 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 6.16 (s, 1H), 4.99 (m, 1H), 4.09(d, J = 8.5 Hz, 1H), 3.94 (m, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.78 (m,1H), 3.68 (t, J = isonicotinamide 10.8 Hz, 1H), 3.58 (t, J = 10.6 Hz,1H), 2.86 (m, 1H), 2.24 (s, 3H). LCMS (m/z) (M + H) = 521.4, Rt = 1.13min. 167

N-(3-((4aS,6S)- 5,5-difluoro-6- hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1H), 8.99(d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 4.8 Hz, 1H), 8.04 (d, J= 1.4 Hz, 1H), 7.73 (dd, J = 8.3, 2.1 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H),7.36 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 6.16 (s, 1H), 4.99 (m, 1H), 4.09(d, J = 8.5 Hz, 1H), 3.94 (m, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.78 (m,1H), 3.68 (t, J = isonicotinamide 10.8 Hz, 1H), 3.58 (t, J = 10.6 Hz,1H), 2.86 (m, 1H), 2.24 (s, 3H). LCMS (m/z) (M + H) = 521.4, Rt = 1.13min. 168

N-(3-((4aR,6R)- 5,5-difluoro-6- hydroxy- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1H), 8.99(d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 4.8 Hz, 1H), 8.04 (d, J= 1.4 Hz, 1H), 7.73 (dd, J = 8.3, 2.1 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H),7.36 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 6.16 (s, 1H), 4.99 (m, 1H), 4.09(d, J = 8.5 Hz, 1H), 3.94 (m, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.78 (m,1H), 3.68 (t, J = isonicotinamide 10.8 Hz, 1H), 3.58 (t, J =10.6 Hz,1H), 2.86 (m, 1H), 2.24 (s, 3H). LCMS (m/z) (M + H) = 521.4, Rt = 1.13min. 169

rac-cis-2-(1,1- difluoroethyl)-N- (3-(6-hydroxy-6- (trifluoromethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.63 (s,1H), 8.88 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J = 4.9 Hz, 1H),7.98 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 8.3, 2.1 Hz, 1H), 7.68 (d, J =2.1 Hz, 1H), 7.35 (d, J = 9.2 Hz, 2H), 6.42 (br s, 1H), 3.93 (m, 3H),3.55 (m, 1H), 3.21 (m, 2H), 2.79 (m, 1H), 2.38 (m, 1H), 2.25 (s, 3H),2.05 (t, J = 19.1 Hz, 3H), 1.80 (m, 1H). LCMS (m/z) (M + H) = 549.1, Rt= 1.42 min. 170

rac-cis-N-(3-(6- hydroxy-6- (trifluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.67 (s, 1H), 9.00(d, J = 5.0 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 5.0 Hz, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.75 (dd, J = 8.3, 2.3 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H),7.36 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 6.42 (s, 1H), 3.93(m, 3H), 3.55 (m, 1H), 3.22 (m, 2H), 2.80 (m, 1H), 2.38 (m, 1H), 2.25(s, 3H), 1.81 (m, isonicotinamide 1H). LCMS (m/z) (M + H) = 553.1, Rt =1.46 min. 171

rac-N-(3-(6- amino- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.68 (s, 1H), 8.99 (d,J = 5.0 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.95-7.83 (m,1H), 7.71 (dd, J = 8.2, 2.1 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.34 (d,J = 8.3 Hz, 1H), 7.19 (d, J = 16.7 Hz, 1H),4.01-3.90 (m, 2H), 3.86 (dd,J = 16.6, 7.5 Hz, 1H), 3.77 (s, 1H), 3.62-3.51 (m, 1H), 3.24 (dd, J =13.5, 7.2 Hz, 2H), 2.75 (td, J = 12.1, 3.5 Hz, 1H), 2.24 (s, 3H),1.81-1.61 (m, 1H). Signal for two exchangeable protons of amine are notobserved, signal for one aliphatic proton is hidden under solvent peak.LCMS (m/z) (M + H) = 484.1, Rt = 1.02 min. 172

rac-N-(4-methyl- 3-(6- propionamido- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)phenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.69 (s, 1H), 8.99 (d,J = 4.9 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.19 (d, J =4.6 Hz, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.70 (s, 1H), 7.68 (d, J = 8.5Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 5.00 (m, 1H), 3.89 (m,3H), 3.57 (q, J = 12.0 11.0 Hz, 1H), 3.22 (dd, ,J = 10.8, 6.3 Hz, 1H),3.11 (t, J = 10.8 Hz, 1H), 2.77 (m, 1H), 2.25 (s, 3H), 2.13 (dq, J =22.6, 7.5 Hz, 2H), 1.80 (d, J = 13.4 Hz, 1H), 1.64 (m, 1H), 1.03 (dt, J= 11.0, 7.6 Hz, 3H). LCMS (m/z) (M + H) = 540.4, Rt = 1.04 min. 173

rac-9-(5-(2-(1,1- difluoroethyl) isonicotinamido)-2- methylphenyl)-N-methyl- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridine-5-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 8.81 (d, J= 4.8 Hz, 1H), 8.11 (s, 1H), 8.05 (m, 1H), 7.96 (d, J = 4.3 Hz, 1H),7.74 (d, J = 15.7 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.25(d, J = 8.2 Hz, 1H), 7.12 (d, J = 6.8 Hz, 1H), 3.85 (d, J = 9.0 Hz, 1H),3.67 (m, 2H), 3.46 (t, J = 11.0 Hz, 1H), 3.09 (dq, J = 29.2, 9.9, 9.5Hz, 2H), 2.89 (m, 2H), 2.73 (t, J = 10.5 Hz, 1H), 2.58 (d, J = 4.4 Hz,3H), 2.54 (m, 1H), 2.16 (s, 3H), 1.98 (t, J = 19.1 Hz, 3H). LCMS (m/z)(M + H) = 522.4, Rt = 0.95 min.

Example 225(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

A vial was charged with(rac)-(4a,10b-trans)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) and2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.05 equiv). THF (0.1 M) and K3PO4 (0.5 M aq, 2 equiv) were added, andthe flask was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos (0.05equiv) were added, and the reaction was heated at 45° C. for 1 h. Thereaction was poured onto water and extracted twice with EtOAc. Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was adsorbed on Celite and purified byflash column chromatography over silica gel (heptane with 0-100% ethylacetate gradient) to give(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid in 90% yield LCMS (m/z) (M+H)=507.1, Rt=1.19 min. ¹HNMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.89 (d, J=5.0 Hz, 1H),8.35-8.25 (m, 1H), 8.19 (s, 1H), 8.04 (d, J=4.8 Hz, 1H), 7.73 (d, J=8.8Hz, 2H), 7.62 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 4.32-4.14 (m, 2H), 4.02(dt, J=13.0, 5.6 Hz, 2H), 3.44 (q, J=10.6 Hz, 2H), 3.05-2.89 (m, 1H),2.58-2.53 (m, 1H), 2.33 (d, J=9.9 Hz, 1H), 2.27 (s, 3H), 2.06 (t, J=19.1Hz, 3H), 1.59 (qd, J=12.4, 4.3 Hz, 1H), 1.17 (t, J=6.9 Hz, 3H).

The following examples were prepared using methods from example 225,using appropriate starting materials.

Example 226(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-cis)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

LCMS (m/z) (M+H)=507.1, Rt=1.14 min. ¹H NMR (400 MHz, DMSO-d6) δ 10.67(s, 1H), 8.89 (d, J=5.0 Hz, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.19 (s, 1H),8.03 (d, J=4.9 Hz, 1H), 7.78-7.67 (m, 3H), 7.35 (d, J=9.0 Hz, 1H), 4.50(d, J=11.0 Hz, 1H), 4.21 (dq, J=13.6, 6.8 Hz, 1H), 4.09 (dq, J=13.7, 6.8Hz, 1H), 3.84 (d, J=11.1 Hz, 1H), 3.52-3.39 (m, 2H), 3.30 (dd, J=11.7,5.7 Hz, 1H), 2.87 (d, J=5.4 Hz, 1H), 2.27 (s, 3H), 2.06 (t, J=19.2 Hz,3H), 1.60 (d, J=10.1 Hz, 1H), 1.50 (qd, J=12.8, 12.4, 4.2 Hz, 1H), 1.18(t, J=6.9 Hz, 3H).

Example 227(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)-6-ethyl-4a-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

LCMS (m/z) (M+H)=521.1, Rt=1.20 min. ¹H NMR (400 MHz, DMSO-d6) δ 10.67(s, 1H), 8.89 (d, J=5.0 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.20 (s, 1H),8.04 (d, J=4.8 Hz, 1H), 7.81-7.65 (m, 3H), 7.35 (d, J=8.3 Hz, 1H), 4.41(d, J=11.2 Hz, 1H), 4.20 (dq, J=13.6, 6.8 Hz, 1H), 4.09 (dq, J=13.6, 6.8Hz, 1H), 3.86 (dd, J=11.1, 3.9 Hz, 1H), 3.42 (t, J=11.1 Hz, 1H), 3.10(d, J=11.3 Hz, 1H), 2.96 (dd, J=12.4, 4.4 Hz, 1H), 2.27 (s, 3H), 2.06(t, J=19.2 Hz, 3H), 1.64 (dd, J=13.3, 4.0 Hz, 1H), 1.44 (qd, J=12.8, 4.6Hz, 1H), 1.16 (t, J=6.9 Hz, 3H), 0.85 (s, 3H).

Examples 228 & 2292-(1,1-difluoroethyl)-N-(3-((4aR,10bS)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideand2-(1,1-difluoroethyl)-N-(3-((4aS,10bR)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamidewas subjected to chiral SFC (Whelk-O1 RR 21×250 mm column, 5-55% MeOH inCO₂ eluent). The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,10bS)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. The second eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aS,10bR)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. NMR and LCMS data for each enantiomer matched that ofthe racemate.

Examples 230 & 2312-(1,1-difluoroethyl)-N-(3-((4aR,10bR)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideand2-(1,1-difluoroethyl)-N-(3-((4aS,10bS)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-cis)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamidewas subjected to chiral SFC (ID 30×250 mm 5 um column, 5-55% IPA in CO₂eluent). The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,10bR)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. The second eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aS,10bS)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. NMR and LCMS data for each enantiomer matched that ofthe racemate.

Examples 232 & 2332-(1,1-difluoroethyl)-N-(3-((4aS,10bS)-6-ethyl-4a-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideand2-(1,1-difluoroethyl)-N-(3-((4aR,10bR)-6-ethyl-4a-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)-6-ethyl-4a-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamidewas subjected to chiral SFC (ID 30×250 mm 5 um column, 5-55% IPA in CO₂eluent). The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aS,10bS)-6-ethyl-4a-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. The second eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4aR,10bR)-6-ethyl-4a-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid. NMR and LCMS data for each enantiomer matched that ofthe racemate.

Example 234:(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

A vial was charged with9-bromo-6-ethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one(1.0 equiv) and2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.05 equiv). Dioxane (0.07 M) and K₃PO₄ (0.5 M aq, 2.0 equiv) wereadded, and the flask was purged with N₂. XPhos Pd G2 (0.05 equiv) andXPhos (0.05 equiv) were added, and the reaction was heated at 90° C. for1 h. The reaction was diluted with DCM, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (DCM and 0-20% MeOH gradient) to provide2-(1,1-difluoroethyl)-N-(3-(6-ethyl-5-oxo-5,6-dihydro-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-9-yl)-4-methylphenyl)isonicotinamideas a white solid in 75% yield. LCMS (m/z) (M+H)=504.2, Rt=0.98 min. ¹HNMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 8.83-8.76 (m, 1H), 8.70 (d,J=2.1 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.21-8.16 (m, 1H), 7.96 (dd,J=5.1, 1.5 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.64 (dd, J=8.3, 2.3 Hz,1H), 7.40 (d, J=8.4 Hz, 1H), 4.14 (bs, 2H), 4.03 (bs, 2H), 2.37 (s, 3H),2.03 (t, J=18.7 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H).

Example 235: “Peak 1” enantiomer ofN-(3-((4a,11b-cis)-7-ethyl-6-oxo-1,4,4a,6,7,11b-hexahydro-2H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

To a mixture of(4a,11b-cis)-10-chloro-4,4a,7,11b-tetrahydro-1H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-6(2H)-one“Peak 1” (1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.1 equiv.), XPhos Pd G2 (5 mol %), and XPhos (5 mol %) under anatmosphere of nitrogen at room temperature was added degassed1,4-dioxane (0.14 M) and degassed aqueous 0.5 M aq. K₃PO₄ (2 equiv.) andthe reaction was heated to 80° C. and stirred for 1 hour. The reactionwas poured into water and extracted three times with ethyl acetate andthree times with dichloromethane. The combined organic phases were driedover MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography (heptane with 0-80% ethylacetate gradient) then HPLC (X-bridge 30×50 mm 5 μm column, water with35-60% acetonitrile gradient, 5 mM NH₄OH) to afford the “Peak 1”enantiomer ofN-(3-((4aS,11bR)-7-ethyl-6-oxo-1,4,4a,6,7,11b-hexahydro-2H-pyrano[4,3-f]pyrido[2,3-d][1,3]oxazepin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid in 71% yield. LCMS (m/z) (M+H)=527.0, Rt=1.18 min. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.97 (d, J=5.02 Hz, 1H), 8.41 (d,J=1.25 Hz, 1H), 8.16 (s, 1H), 8.12 (br s, 1H), 7.99 (br d, J=4.52 Hz,1H), 7.67 (br s, 2H), 7.62 (br d, J=8.28 Hz, 1H), 7.39 (d, J=8.28 Hz,1H), 4.83 (br t, J=8.28 Hz, 1H), 4.04-4.26 (m, 2H), 3.78-3.96 (m, 3H),3.41-3.52 (m, 2H), 2.26-2.40 (m, 4H), 2.05-2.21 (m, 1H), 1.34 (t, J=7.03Hz, 3H).

Example 236:N-(3-((4aR,10bS)-6-ethyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

(4aR,10bS)-9-Bromo-6-ethyl-1,2,4,4a,6,10b-hexahydro-5H-pyrano[3,4-c][1,8]naphthyridin-5-one(1 equiv) was combined withN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.05 equiv) and dissolved into dioxane (0.085 M) along with K₃PO₄solution (0.5M aqueous, 2 equiv) in a round bottom flask with a watercondenser and nitrogen atmosphere. Suspension was degassed by spargingwith nitrogen gas for 15 minutes. X-Phos Pd G2 (0.05 equiv) and X-Phos(0.05 equiv) were added and then the reaction mixture was heated with apre-heated oil bath to 80° C. for 16 hr. After this time the reactionwas diluted with EtOAc and treated with anhydrous granular Na₂SO₄.Reaction was filtered and volatiles removed to yield a crude brown oilwhich was purified by flash column chromatography over silica gel(heptane and 0-60% EtOAc gradient) to giveN-(3-((4aR,10bS)-6-ethyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid in 78% yield. LCMS (m/z) (M+H)=511.1985, Rt=3.89 min.¹H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J=5.0 Hz, 1H), 8.30 (s, 1H),8.28-8.24 (m, 1H), 8.16-8.08 (m, 1H), 7.69-7.60 (m, 3H), 7.35 (d, J=9.1Hz, 1H), 4.41 (dd, J=11.6, 4.5 Hz, 1H), 4.29 (dt, J=13.9, 6.9 Hz, 1H),4.12 (dq, J=13.9, 7.0 Hz, 2H), 3.63-3.45 (m, 2H), 2.97 (s, 1H), 2.49(ddd, J=14.8, 10.5, 4.5 Hz, 1H), 1.73 (qd, J=12.4, 4.6 Hz, 1H),1.48-1.42 (m, 2H), 1.30-1.13 (m, 5H).

The following were prepared using the same methods as described forExample 234-236 above using the appropriate starting materials. Productswere purified by flash column chromatography over silica gel, HPLC,and/or SFC methods as appropriate:

Ex. No. Structure Name Physical Data 237

N-(3-(6-ethyl-5- oxo-5,6-dihydro- 4H-pyrido[2,3- b][1,2,4]triazo1o[4,3-d][1,4]diazepin- 9-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 8.91 (d, J= 5.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 2.1Hz, 1H), 8.12 (dd, J = 5.0, 1.2 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.64(dd, J = 8.3, 2.3 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.14 (bs, 2H), 4.03(s, 2H), 2.37 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M+ H) =508.2, Rt = 1.00 min 238

N-(5-(6-ethyl-5- oxo-5,6-dihydro- 4H-pyrido[2,3- b][1,2,4]triazo1o[4,3-d][1,4]diazepin- 9-yl)-6- methylpyridin-3- yl)-3- (trifluoromethyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 8.83 (d, J = 2.4Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 10.4, 2.3 Hz, 2H), 8.31(s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.76 (t, J= 7.8 Hz, 1H), 4.15 (s, 2H), 4.05 (s, 2H), 2.58 (s, 3H), 1.30 (t, J =7.0 Hz, 3H). LCMS (m/z) (M + H) = 508.2, Rt = 0.93 min 239

N-(3-(6-ethyl-4,4- dimethyl-5-oxo- 5,6-dihydro-4H- pyrido[2,3-b][1,2,4]-triazolo[4, 3-d][1,4]diazepin- 9-yl)-4 methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.09(s, 1H), 8.91 (d, J = 5.0 Hz, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.31 (s,1H), 8.24 (d, J = 1.9 Hz, 1H), 8.13 (d, J = 4.6 Hz, 1H), 7.85 (d, J =2.0 Hz, 1H), 7.66 (dd, J = 8.3, 2.0 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H),4.09-4.20 (m, 2 h), 2.36 (s, 3H), 1.88 (s, 3H), 1.33 (t, J = 6.9 Hz,3H), 1.25 (s, 3H). LCMS (m/z) (M + H) = 536.2, Rt = 1.13 min 240

N-(5-(6-ethyl-4,4- dimethyl-5-oxo- 5,6-dihydro-4H- pyrido[2,3-b][1,2,4]triazolo[4, 3-d][1,4]diazepin- 9-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 9.11 (s,1H), 8.83 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.34 (dd, J =10.9, 2.3 Hz, 2H), 8.31 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.93 (d, J =7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 4.10-4.30 (m, 2 H), 2.58 (s, 3H),1.91 (s, 3H), 1.35 (t, J = 6.9 Hz, 4H), 1.25 (s, 3H). LCMS (m/z) (M + H)= 536.2, Rt = 1.02 min 241

N-(3-(5-ethyl-6- oxo-5,6-dihydro- 4H-pyrido[2,3- f][1,2,4]-triazolo[4,3-a][1,4]diazepin-9- yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.91 (d, J= 5.0 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 1.7 Hz, 2H), 8.13(dd, J = 5.0, 1.2 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.3,2.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.84 (s, 2H), 3.80 (q, J = 7.0Hz, 2H), 2.37 (s, 3H), 1.27 (t, J = 7.2 Hz, 4H). LCMS (m/z) (M + H) =508.1, Rt = 0.83 min 242

N-(3-(7-ethyl-11b- methyl-6-oxo- 1,2,4,6,7,11b- hexahydro-[1,3]oxazino[3,4- c]quinazolin-10- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.15-8.08 (m, 1H), 7.62 (d, J = 7.3Hz, 2H), 7.35-7.27 (m, 2H), 7.23 (d, J = 1.8 Hz, 1H), 7.12 (d, J = 8.4Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.63 (d, J = 10.0 Hz, 1H), 4.16-3.86 (m, 4H), 2.28 (s, 3H), 2.25- 2.11 (m, 2H), 1.58 (s, 3H), 1.28 (t, J= 7.0 Hz, 3H). LCMS (m/z) (M + H) = 525.2, Rt = 1.24 min 243

N-(5-(7-ethyl-11b- methyl-6-(mo- 1,2,4,6,7,11b- hexahydro-[1,3]oxazino[3,4- c]quinazolin-10- yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J =2.4 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 2.4Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.37 (dd, J= 8.4, 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H),5.59 (d, J = 10.1 Hz, 1H), 4.64 (d, J = 10.0 Hz, 1H), 4.17- 3.88 (m,4H), 2.50 (s, 3H), 2.31- 2.15 (m, 2H), 1.59 (s, 3H), 1.28 (t, J = 7.0Hz, 3H). LCMS (m/z) (M + H) = 525.3, Rt = 1.04 min 244

N-(3-(7-ethyl-11b- methyl-6-oxo- 1,2,4,6,7,11b- hexahydro-[1,3]oxazino[3,4- c]quinazolin-10- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.15-8.07 (m, 1H), 7.61 (s, 2H), 7.30(dt, J = 8.9, 2.0 Hz, 2H), 7.23 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 8.5Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.63 (d, J = 10.0 Hz, 1H), 4.16-3.87 (m, 4H), 2.27 (s, 3H), 2.25- 2.13 (m, 2H), 1.58 (s, 3H), 1.27 (q, J= 6.6, 6.1 Hz, 4H). LCMS (m/z) (M + H) = 525.3, Rt = 1.23 min 245

N-(5-(7-ethyl-11b- methyl-6-oxo- 1,2,4,6,7,11b- hexahydro-[1,3]oxazino[3,4- c]quinazolin-10- yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J =2.4 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 2.4Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.37 (dd, J= 8.4, 1.9 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H),5.59 (d, J = 10.0 Hz, 1H), 4.64 (d, J = 10.0 Hz, 1H), 4.17- 3.83 (m,4H), 2.50 (s, 3H), 2.28- 2.13 (m, 2H), 1.59 (s, 3H), 1.28 (t, J = 7.0Hz, 3H). LCMS (m/z) (M + H) = 525.3, Rt = 1.04 min 246

N-(3-((5a, 11b-cis)- 7-ethyl-6-oxo- 1,2,4,5,5a,6,7,11b- octahydrooxepino[4,5- c][1,8]naphthyridin- 10-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J = 5.0 Hz,1H), 8.30 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.16- 8.08 (m, 1H),7.70-7.61 (m, 3H), 7.34 (d, J = 8.1 Hz, 1H), 4.30 (dq, J = 13.9, 7.0 Hz,1H), 4.18 (dq, J = 13.9, 7.0 Hz, 1H), 3.97 (ddd, J = 12.8, 9.4, 3.7 Hz,1H), 3.84-3.65 (m, 3H), 3.33 (m, 1H), 3.09 (q, J = 4.8 Hz, 1H), 2.45(dq, J = 13.5, 4.4 Hz, 1H), 2.30 (s, 3H), 1.99 (dtq, J = 14.6, 9.5, 4.9Hz, 2H), 1.83-1.69 (m, 1H), 1.24 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M ++)H) = 525.3, Rt = 1.21 min 247

N-(3-((5a, 11b-cis)- 7-ethyl-6-oxo- 1,2,4,5,5a,6,7,11b- octahydrooxepino4,5- c][1,8]naphthyridin- 10-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J = 5.0 Hz,1H), 8.30 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.15- 8.07 (m, 1H),7.71-7.60 (m, 3H), 7.34 (d, J = 8.1 Hz, 1H), 4.30 (dq, J = 13.9, 7.0 Hz,1H), 4.18 (dq, J = 13.9, 7.0 Hz, 1H), 3.97 (ddd, J = 12.8, 9.4, 3.7 Hz,1H), 3.87-3.64 (m, 3H), 3.33 (m, 1H), 3.09 (q, J = 4.8 Hz, 1H), 2.45(dq, J = 13.5, 4.4 Hz, 1H), 2.30 (s, 3H), 1.99 (dtq, J = 20.0, 9.5, 4.9Hz, 2H), 1.77 (dq, J = 14.8, 3.1 Hz, 1H), 1.24 (t, J = 7.0 Hz, 3H). LCMS(m/z) (M + H) = 525.3, Rt = 1.21 min 248

N-(3-((5a, 11b- trans)-7-ethyl-6- oxo- 1,2,4,5,5a,6,7,11b-octahydrooxepino 4,5- c][1,8]naphthyridin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91 (d,J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.27-8.22 (m, 1H), 8.12 (dd, J = 5.0, 1.2Hz, 1H), 7.75 -7.70 (m, 1H), 7.66 (dq, J = 4.5, 2.3 Hz, 2H), 7.39-7.33(m, 1H), 4.32 (dq, J = 13.9, 6.9 Hz, 1H), 4.17 (dq, J = 13.9, 7.0 Hz,1H), 3.97 (dt, J = 12.1, 4.1 Hz, 2H), 3.89 - 3.75 (m, 2H), 2.98 (td, J =12.3, 10.3, 4.3 Hz, 1H), 2.73 (dq, J = 15.5, 3.3 Hz, 1H), 2.65- 2.51(m,2H), 2.30 (s, 3H), 2.10 (dddd, J = 15.7, 11.4, 9.2, 4.4 Hz, 1H),2.02-1.89 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 525.3,Rt = 1.24 min 249

N-(3-((5a, 11b- trans)-7-ethyl-6- oxo- 1,2,4,5,5a,6,7,11boctahydrooxepino [4,5- c][1,8]naphthyridin- 4,5- 10-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.91 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.26-8.21 (m,1H), 8.15-8.07 (m, 1H), 7.72 (s, 1H), 7.66 (dq, J = 4.5, 2.2 Hz, 2H),7.39-7.29 (m, 1H), 4.32 (dq, J = 13.9, 6.9 Hz, 1H), 4.17 (dq, J = 13.9,7.0 Hz, 1H), 3.97 (dt, J = 12.1, 4.0 Hz, 2H), 3.90- 3.71 (m, 2H),3.04-2.92 (m, 1H), 2.73 (dq, J = 15.5, 3.3 Hz, 1H), 2.64- 2.50 (m, 2H),2.30 (s, 3H), 2.16- 2.04 (m, 1H), 2.02-1.93 (m, 1H), 1.26 (t, J = 7.0Hz, 3H). LCMS (m/z) (M + H) = 525.3, Rt = 1.24 min 250

N-(5-((5a, 11b- trans)-7-ethyl-6- oxo- 1,2,4,5,5a,6,7,11b-octahydrooxepino [4,5- c][1,8]naphthyridin- 10-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.84(d,J = 2.4 Hz,1H),8.34- 8.29 (m, 2H), 8.24 (d, J = 7.9 Hz, 1H), 8.17 (d,J = 2.4 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.81-7.78 (m, 1H), 7.75 (t, J= 7.8 Hz, 1H), 4.33 (dq, J = 13.9, 7.0 Hz, 1H), 4.18 (dq, J = 13.9, 7.0Hz, 1H), 3.97 (dt, J = 6.8, 3.5 Hz, 2H), 3.91-3.82 (m, 1H), 3.82-3.75(m, 1H), 3.00 (td, J = 12.2, 10.3, 4.3 Hz, 1H), 2.73 (dq, J = 15.5, 3.3Hz, 1H), 2.65-2.54 (m, 2H), 2.51 (s, 3H), 2.11 (dddd, J = 15.7, 11.4,9.3, 4.5 Hz, 1H), 2.05- 1.92 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H). LCMS(m/z) (M + H) = 525.1, Rt = 1.12 min 251

N-(5-((5a, 11b- trans)-7-ethyl-6- oxo- 1,2,4,5,5a, 6,7,11b-octahydrooxepino [4,5- c[1,8]naphtliyridin- 10-yl)-6- methylpyridin-3-yl)-2-(2- fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.84 (d, J = 2.4 Hz, 1H), 8.72 (d, J = 5.1 Hz, 1H),8.34-8.28 (m, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.80 (dd, J =5.3, 1.6 Hz, 2H), 4.33 (dq, J = 13.9, 6.9 Hz, 1H), 4.17 (dq, J = 13.9,7.0 Hz, 1H), 3.96 (dt, J = 7.2, 3.8 Hz, 2H), 3.91-3.82 (m, 1H), 3.77(dd, J = 11.7, 3.4 Hz, 1H), 2.99 (td, J = 12.2, 10.4, 4.2 Hz, 1H), 2.73(dq, J = 15.5, 3.3 Hz, 1H), 2.66- 2.53 (m, 2H), 2.10 (dddd, J = 15.7,11.4, 9.4, 4.5 Hz, 1H), 1.98 (dtd, J = 14.1, 10.7, 3.2 Hz, 1H), 1.76 (s,3H), 1.70 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 518.2.Rt = 1.00 min 252

N-(5-((4aS, 10bR)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.93(d, J = 5.0 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.37-8.29 (m, 2H), 8.19(d, J = 2.4 Hz, 1H), 8.17-8.11 (m, 1H), 7.70 (s, 1H), 4.41 (dd, J =11.6, 4.5 Hz, 1H), 4.30 (dq, J = 13.8, 6.9 Hz, 1H), 4.13 (dq, J = 13.8,6.9 Hz, 2H), 3.63-3.46 (m, 2H), 2.99 (s, 1H), 2.59-2.45 (m, 4H),2.38-2.26 (m, 1H), 1.74 (qd, J = 12.5, 4.6 Hz, 1H), 1.25 (t, J = 7.0 Hz,3H). LCMS (m/z) (M + H) = 512.1, Rt = 0.97 min 253

N-(3-((4aS, 10bR)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin 9-yl)-4- methylphenyl)-3- fluoro-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.65(d, J = 4.7 Hz, 1H), 8.28- 8.19 (m, 1H), 7.96 (t, J = 4.8 Hz, 1H), 7.61(d, J = 8.3 Hz, 3H), 7.35 (d, J = 8.0 Hz, 1H), 4.41 (dd, J = 11.6, 4.5Hz, 1H), 4.29 (dq, J = 13.9, 7.0 Hz, 1H), 4.12 (dq, J = 13.9, 7.0 Hz,2H), 3.63-3.49 (m, 2H), 2.96 (s, 1H), 2.49 (ddd, J = 14.7, 10.5, 4.5 Hz,1H), 2.37-2.25 (m, 4H), 1.73 (qd, J = 12.4, 4.6 Hz, 1H), 1.24 (t, J =7.0 Hz, 3H). LCMS (m/z) (M + H) = 529.1, Rt = 1.26 min 254

N-(3-((4aS, 10bR)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.69 (d, J = 5.1 Hz, 1H), 8.31- 8.23 (m, 1H), 8.06 (s, 1H), 7.77 (dd, J= 5.1, 1.7 Hz, 1H), 7.67-7.59 (m, 3H), 7.34 (d, J = 9.1 Hz, 1H), 4.41(dd, J = 11.6, 4.5 Hz, 1H), 4.30 (dq, J = 13.9, 7.0 Hz, 1H), 4.13 (dq, J= 13.9, 6.9 Hz, 2H), 3.67-3.49 (m, 2H), 2.97 (s, 1H), 2.49 (ddd, J =14.7, 10.5, 4.5 Hz, 1H), 2.37-2.28 (m, 4H), 1.73 (m, 7H), 1.25 (t, J =7.0 Hz, 3H). LCMS (m/z) (M + H) = 503.1, Rt = 1.22 min 255

N-(5-((4aR, 10bS)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-2-fluoro-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 2.1, 0.7 Hz, 1H),8.14 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 14.2, 1.3 Hz, 1H), 7.91 (t, J =7.3 Hz, 1H), 7.71- 7.64 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.41 (dd, J =11.6, 4.5 Hz, 1H), 4.30 (dq, J = 13.9, 6.9 Hz, 1H), 4.13 (dq, J = 14.2,7.1 Hz, 2H), 3.63- 3.48 (m, 2H), 3.04-2.92 (m, 1H), 2.56-2.44 (m, 4H),2.37-2.30 (m, 1H), 1.74 (qd, J = 12.5, 4.6 Hz, 1H), 1.24 (td, J = 7.1,4.1 Hz, 3H). LCMS (m/z) (M + H) = 529.2, Rt = 1.05 min 256

N-(5-((4aS, 10bR)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-2-fluoro-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 2.1, 0.8 Hz, 1H),8.14 (d, J = 2.5 Hz, 1H), 8.06-7.98 (m, 1H), 7.93- 7.86 (m, 1H),7.73-7.65 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.41 (dd, J = 11.6, 4.5 Hz,1H), 4.30 (dq, J = 13.9, 7.0 Hz, 1H), 4.13 (dq, J = 14.1, 7.1 Hz, 2H),3.62-3.48 (m, 2H), 3.03-2.93 (m, 1H), 2.58-2.43 (m, 4H), 2.37-2.29 (m,1H), 1.74 (qd, J = 12.5, 4.6 Hz, 1H), 1.24 (td, J = 7.1, 4.0 Hz, 3H).LCMS (m/z) (M + H) = 529.3, Rt = 1.05 min 257

N-(3-((4aS, 10bR)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO-d6) δ10.90 (s, 1H), 9.92 (d, J = 1.7 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.36-8.22 (m, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.62 (s, 1H), 7.39 (d, J = 8.7Hz, 1H), 4.26 (dd, J = 11.4, 4.4 Hz, 1H), 4.17 (dt, J = 13.5, 6.8 Hz,1H), 4.01 (dq, J = 13.9, 6.5 Hz, 2H), 3.44 (q, J = 10.5 Hz, 2H),3.05-2.94 (m, 1H), 2.28 (s, 4H), 1.59 (qd, J = 12.4, 4.3 Hz, 1H), 1.18(t, J = 7.0 Hz, 4H). LCMS (m/z) (M + H) = 512.0, Rt = 1.17 min 258

N-(3-((4aS, 10bR)- 6-(2-hydroxyethyl)- 5-oxo- 2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.12 (d, J= 4.9 Hz, 1H), 7.68-.61 (m, 3H), 7.35 (d, J = 9.0 Hz, 1H), 4.53- 4.46(m, 1H), 4.41 (dd, J = 11.7, 4.5 Hz, 1H), 4.24-4.17 (m, 1H), 4.17- 4.10(m, 1H), 3.82-3.76 (m, 2H), 3.63-3.49 (m, 2H), 3.08-2.96 (m, 1H), 2.53(ddd, J = 14.7, 10.5, 4.5 Hz, 1H), 2.33 (d, J = 12.8 Hz, 1H), 2.29 (s,3H), 1.80-1.67 (m, 1H). LCMS (m/z) (M + H) = 527.0, Rt = 1.05 min 259

N-(5-((4aS, 10bR)- 6-(2-hydroxyethyl)- 5-oxo- 2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide 1H NMR (400 MHz, Methanol-d4) δ 8.83(d, J = 2.4 Hz, 1H), 8.35- 8.27 (m, 2H), 8.24 (d, J = 8.0 Hz, 1H), 8.17(d, J = 2.4 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H),7.71 (s, 1H), 4.50 (dt, J = 12.1, 6.0 Hz, 1H), 4.42 (dd, J = 11.7, 4.5Hz, 1H), 4.25-4.18 (m, 1H), 4.18-4.10 (m, 1H), 3.79 (td, J = 6.1, 2.0Hz, 2H), 3.63-3.49 (m, 2H), 3.04 (s, 1H), 2.61-2.53 (m, 1H), 2.51 (s,3H), 1.75 (qd, J = 12.4, 4.6 Hz, 1H). LCMS (m/z) (M + H) = 527.3, Rt =0.86 min 260

2-(2-fluoropropan- 2-yl)-N-(5-((4aS, 10bR)-66-(2- hydroxyethyl)-5-oxo-2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin-9-yl)-6- methylpyridin-3- yl)isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.84 (d, J = 2.5 Hz, 1H), 8.74- 8.69 (m, 1H), 8.31 (dd, J= 2.1, 0.8 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 8.09 (s, 1H), 7.80 (dd, J= 5.1, 1.7 Hz, 1H), 7.70 (dd, J = 2.1, 1.4 Hz, 1H), 4.55-4.45 (m, 1H),4.42 (dd, J = 11.6, 4.5 Hz, 1H), 4.26-4.19 (m, 1H), 4.19-4.11 (m, 1H),3.79 (td, J = 6.2, 2.2 Hz, 2H), 3.63-3.50 (m, 2H), 3.09-2.99 (m, 1H),2.60-2.53 (m, 1H), 2.51 (s, 3H), 2.35 (d, J = 13.1 Hz, 1H), 1.80 (d, J =4.5 Hz, 1H), 1.76 (s, 3H), 1.70 (d, J = 1.3 Hz, 3H). LCMS (m/z) (M + H)= 520.2, Rt = 0.76 min 261

N-(3-((4aS, 10bR)- 6-isopropyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.73 (s,1H), 9.00 (d, J = 4.9 Hz, 1H), 8.37 (s, 1H), 8.31-8.25 (m, 1H), 8.20 (d,J = 4.6 Hz, 1H), 7.72 (d, J = 6.7 Hz, 2H), 7.60 (s, 1H), 7.37 (d, J =8.9 Hz, 1H), 5.23 (p, J = 6.8 Hz, 1H), 4.22 (dd, J = 11.4, 4.4 Hz, 1H),4.02 (dd, J = 11.0, 3.3 Hz, 1H), 3.52-3.30 (m, 3H), 3.03-2.86 (m, 1H),2.44 (ddd, J = 14.6, 10.6, 4.6 Hz, 1H), 2.28 (s, 3H), 1.63- 1.53 (m,1H), 1.51 (d, J = 6.9 Hz, 3H), 1.44 (d, J = 6.8 Hz, 3H). LCMS (m/z) (M +H) = 525.2, Rt = 1.33 min 262

N-(5-((4aS, 10bR)- 6-isopropyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.84 (d, J =2.5 Hz, 1H), 8.35- 8.28 (m, 2H), 8.23 (t, J = 8.2 Hz, 1H), 8.17 (d, J=+) 2.4 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75 (td, J = 7.8, 3.7 Hz,1H), 7.67 (dd, J = 2.1, 1.3 Hz, 1H), 5.31 (hept, J = 6.9 Hz, 1H), 4.37(dd, J = 11.7, 4.6 Hz, 1H), 4.13 (dd, J = 11.5, 3.7 Hz, 1H), 3.53 (ddd,J = 24.6, 11.7, 10.5 Hz, 2H), 2.95 (s, 1H), 2.52 (d, J = 4.0 Hz, 4H),2.42 (ddd, J = 14.7, 10.5, 4.6 Hz, 1H), 2.34-2.27 (m, 1H), 1.72 (qd, J =12.5, 4.6 Hz, 1H), 1.57 (d, J = 6.9 Hz, 4H), 1.50 (d, J = 6.9 Hz, 3H).LCMS (m/z) (M + H) = 524.9, Rt = 1.13 min 263

2-(1,1- difluoroethyl)-N- (3-((4aS, 10bR)-6- isopropyl-5-oxo-2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4-methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.69 (bs, 1H), 8.89 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 8.04 (d, J =4.4 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.60 (s, 1H), 7.36 (d, J = 8.1Hz, 1H), 5.23 (p, J = 6.7 Hz, 1H), 4.22 (dd, J = 11.3, 4.2 Hz, 1H), 4.02(d, J = 8.0 Hz, 1H), 3.52-3.27 (m, 2H), 2.95 (t, J = 11.2 Hz, 1H),2.47-2.38 (m, 1H), 2.28 (s, 4H), 2.06 (t, J = 19.1 Hz, 4H), 1.62-1.55(m, 1H), 1.52 (d, J = 6.8 Hz, 3H), 1.44 (d, J = 6.8 Hz, 3H). LCMS (m/z)(M + H) = 521.1, Rt = 1.30 min 264

N-(3-((4aS, 10bR)- 6-(2,2- difluoroethyl)-5- oxo-2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.32- 8.21 (m, 2H), 8.12 (d, J = 4.9 Hz, 1H), 7.66(d, J = 8.0 Hz, 3H), 7.35 (d, J = 8.0 Hz, 1H), 6.23 (t, J =+) 4.4 Hz,1H), 4.81 (tdd, J = 15.1, 10.1, 5.4 Hz, 1H), 4.41 (dd, J = 11.5, 4.4 Hz,1H), 4.34 (dtd, J = 14.1, 7.9, 7.1, 3.2 Hz, 1H), 4.14 (dd, J = 11.5, 3.8Hz, 1H), 3.68-3.47 (m, 2H), 3.02 (s, 1H), 2.57 (ddd, J = 14.6, 10.5, 4.5Hz, 1H), 2.40-2.32 (m, 1H), 2.29 (s, 3H), 1.75 (qd, J = 12.4, 4.5 Hz,1H). LCMS (m/z) (M + H) = 547.2, Rt = 1.24 min 265

2-(1,1- difluoroethyl)-N- (3-((4aS, 10bR)-6- (2,2-difluoroethyl)- 5-oxo-2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)4-methylphenyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.81 (d, J= 5.0 Hz, 1H), 8.33-8.25 (m, 1H), 8.18 (s, 1H), 7.97 (d, J = 4.5 Hz,1H), 7.66 (d, J = 8.4 Hz, 3H), 7.35 (d, J = 8.0 Hz, 1H), 6.24 (t, J =4.4 Hz, 1H),4.81 (tdd, J = 15.1, 10.1, 5.4 Hz, 1H), 4.42 (dd, J = 11.5,4.4 Hz, 1H), 4.34 (dddd, J = 13.9, 11.6, 7.0, 3.0 Hz, 1H), 4.14 (dd, J =11.5, 3.8 Hz, 1H), 3.59 (d, J = 13.0 Hz, 1H), 3.53 (d, J = 11.4 Hz, 1H),3.03 (s, 1H), 2.57 (ddd, J = 14.6, 10.5, 4.5 Hz, 1H), 2.40-2.32 (m, 1H),2.30 (s, 3H), 2.04 (t, J = 18.7 Hz, 3H), 1.75 (qd, J = 12.4, 4.5 Hz,1H). LCMS (m/z) (M + H) = 543.2, Rt = 1.22 min 266

N-(5-((4aS, 10bR)- 6-(2,2- difluoroethyl)-5- oxo-2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.84(d, J = 2.4 Hz, 1H), 8.36- 8.32 (m, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.9Hz 1H), 8.18 (d, J = 2.3 Hz 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.79- 7.67(m, 2H), 6.24 (t, J = 4.4 Hz, 1H), 4.81 (ddt, J = 15.0, 10.2, 5.1 Hz,1H), 4.42 (dd, J = 11.8, 4.4 Hz, 1H), 4.40-4.27 (m, 1H), 4.15 (dd, J =11.5, 3.8 Hz, 1H), 3.56 (q, J = 12.1, 11.4 Hz, 2H), 3.04 (s, 1H), 2.59(ddd, J = 14.6, 10.5, 4.5 Hz, 1H), 2.51 (s, 3H), 2.37 (d, J = 13.4 Hz,1H), 1.77 (qd, J = 12.4, 4.5 Hz, 1H). LCMS (m/z) (M + H) = 547.2, Rt =1.10 min 267

2-(1,1- difluoroethyl)-N- (3-((4aS, 10bR)-6- (2-hydroxyethyl)-5-oxo-2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin-9-yl)-4- methylphenyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ8.80 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.17 (s, 1H), 7.96(d, J = 5.0 Hz, 1H), 7.70-7.56 (m, 3H), 7.34 (d, J = 9.2 Hz, 1H), 4.49(dt, J = 13.2, 5.9 Hz, 1H), 4.41 (dd, J = 11.7, 4.5 Hz, 1H), 4.20 (dt, J= 13.3, 6.6 Hz, 1H), 4.16-4.09 (m, 1H), 3.79 (td, J = 6.2, 1.6 Hz, 2H),3.64-3.49 (m, 2H), 3.08-2.97 (m, 1H), 2.53 (ddd, J = 14.6, 10.5, 4.5 Hz,1H), 2.37-2.31 (m, 1H), 2.29 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H), 1.74(qd, J = 12.4, 4.6 Hz, 1H). LCMS (m/z) (M + H) = 523.1, Rt = 1.02 min268

N-(3-((6aS, 6bS, 9aS, 9bS)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 8.16- 8.08 (m, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.58 (d, J = 1.6Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.30 (q, J = 6.9 Hz, 2H), 4.16 (dd, J= 15.0, 9.7 Hz, 2H), 3.53 (ddd, J = 14.8, 9.7, 5.1 Hz, 2H), 3.49-3.43(m, 1H), 3.17 (td, J = 10.8, 9.3, 6.0 Hz, 2H), 2.95- 2.86 (m, 1H), 2.29(s, 3H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 523.2, Rt = 1.18min 269

2-(1,1- difluoroethyl)-N- (3-((6aS, 6bS, 9aS, 9bS)-5-ethyl-6-oxo-5,6,6a,6b,7,9,9a,9b- octahydrofuro[3′,4′: 3,4]cyclobuta[1,2-c][1,8]naphthyridin- 2-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400MHz, Methanol-d4) δ 8.80 (d, J = 5.0 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H),7.96 (d, J = 4.3 Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 1.6 Hz,1H), 7.33 (d, J = 7.9 Hz, 1H), 4.30 (q, J = 6.9 Hz, 2H), 4.16 (dd, J =15.7, 9.7 Hz, 2H), 3.54 (td, J = 9.6, 4.8 Hz, 2H), 3.50-3.43 (m, 1H),3.17 (td, J = 10.9, 9.3, 6.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.28 (s, 3H),2.03 (t, J = 18.7 Hz, 3H), 1.25 (t, J = 6.9 Hz, 3H). LCMS (m/z) (M + H)= 519.2, Rt = 1.15 min 270

N-(3-((6aR, 6bR, 9aR, 9bR)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.93 (d, J = 5.0 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J = 2.1Hz, 1H), 8.17- 8.12 (m, 1H), 7.67 (d, J = 7.3 Hz, 2H), 7.62-7.57 (m,1H), 7.36 (d, J = 8.8 Hz, 1H), 4.32 (q, J = 7.0 Hz, 2H), 4.19 (dd, J =15.0, 9.7 Hz, 2H), 3.56 (td, J = 9.6, 4.8 Hz, 2H), 3.50 (dd, J = 9.3,4.5 Hz, 1H), 3.25-3.13 (m, 2H), 2.98-2.90 (m, 1H), 2.31 (s, 3H), 1.28(t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 523.2, Rt = 1.18 min 271

2-(1,1- difluoroethyl)-N- (3-((6aR, 6bR, 9aR, 9bR)-5-ethyl-6- oxo-5,6,6a,6b,7,9,9a,9b- octahydrofuro[3′,4′: 3,4]cyclobuta[1,2-c][1,8]naphthyridin 2-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400MHz, Methanol-d4) δ 8.85-8.80 (m, 1H), 8.27 (d, J = 2.2 Hz, 1H),8.22-8.15 (m, 1H), 7.98 (dd, J = 5.0, 1.5 Hz, 1H), 7.66 (d, J = 7.5 Hz,2H), 7.63-7.56 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 4.32 (q, J = 7.0 Hz,2H), 4.19 (dd, J = 15.7, 9.7 Hz, 2H), 3s.56 (td, J = 9.6, 4.8 Hz, 2H),3.52-3.45 (m, 1H), 3.24-3.13 (m, 2H), 3.01-2.89 (m, 1H), 2.31 (s, 3H),2.05 (t, J = 18.7 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H)= 519.2, Rt = 1.16 min 272

N-(5-((6aS, 6bS, 9aS, 9bS)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-6-methylpyridin-3- yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz,Methanol-d4) δ 8.73 (d, J = 2.4 Hz, 1H), 8.22 (q, J = 3.6, 2.5 Hz, 2H),8.15 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 7.8 Hz,1H), 7.66 (t, J = 7.8 Hz, 1H), 7.57 (dd, J = 2.2, 0.7 Hz, 1H), 4.22 (q,J = 7.0 Hz, 2H), 4.11 (d, J = 9.6 Hz, 1H), 4.06 (d, J = 9.7 Hz, 1H),3.44 (ddt, J = 19.5, 9.6, 4.4 Hz, 3H), 3.16-3.06 (m, 2H), 2.88-2.81 (m,1H), 2.42 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 523.9,Rt = 0.93 min 273

N-(3-((6aS, 6bS, 9aS, 9bS)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-3- fluoro-2- (trifluoromethyl) isonicotinamide ¹H NMR (400MHz, Methanol-d4) δ 8.65 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H),7.95 (t, J = 4.8 Hz, 1H), 7.63-7.55 (m, 3H), 7.33 (d, J = 8.2 Hz 1H),4.30 (q, J = 7.0 Hz, 2H), 4.16 (dd, J = 15.9, 9.7 Hz, 2H), 3.53 (ddd, J= 14.9, 9.7, 5.2 Hz, 2H), 3.47 (dd, J = 9.5, 4.3 Hz, 1H), 3.23-3.11 (m,2H), 2.94-2.89 (m, 1H), 2.28 (d, J = 3.5 Hz, 3H), 1.25 (t, J = 7.0 Hz,3H). LCMS (m/z) (M + H) = 541.1, Rt = 1.13 min 274

N-(3-((6aS, 6bS, 9aS, 9bS)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-5- (trifluoromethyl) nicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 9.38-9.30 (m, 1H), 9.11-9.02 (m, 1H), 8.66 (s, 1H), 8.24(d, J = 2.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 1.6 Hz, 1H),7.32 (d , J = 8.0 Hz, 1H), 4.30 (q, J = 6.9 Hz, 2H), 4.16 (dd, J = 15.5,9.7 Hz, 2H), 3.53 (ddd, J = 14.7, 9.7, 5.1 Hz, 2H), 3.47 (dd, J = 9.5,4.3 Hz, 1H), 3.18 (ddd, J = 14.3, 10.7, 4.8 Hz, 2H), 2.98-2.85 (m, 1H),2.28 (s, 3H), 1.25 (t, J = 6.9 Hz, 3H). LCMS (m/z) (M + H) = 523.1, Rt =1.09 min 275

N-(5-((6aR, 6bR, 9aR, 9bR)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-6-methylpyridin-3- yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz,Methanol-d4) δ 8.82 (d, J = 2.4 Hz, 1H), 8.33- 8.28 (m, 2H), 8.24 (d, J= 8.0 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.92 J = 78 Hz, 1H), 7.75 (t, J= 7.8 Hz, 1H), 7.66 (dd, J = 2.2, 0.7 Hz, 1H), 4.31 (q, J = 7.0 Hz, 2H),4.17 (dd, J = 19.1, 9.7 Hz, 2H), 3.53 (ddt, J = 15.7, 11.0, 5.5 Hz, 4H),3.19 (ddd, J = 13.4, 8.4, 3.7 Hz, 2H), 2.97-2.87 (m, 1H), 2.51 (s, 3H),1.26 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 523.3, Rt = 1.03 min 276

N-(3-((6aR, 6bR, 9aR, 9bR)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-3- fluoro-2- (trifluoromethyl) isonicotinamide 1H NMR (400MHz, Methanol-d4) δ 8.65 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H),7.95 (t, J = 4.8 Hz, 1H), 7.64-7.55 (m, 3H), 7.33 (d, J = 8.2 Hz, 1H),4.30 (q, J = 7.0 Hz, 2H), 4.16 (dd, J = 16.0, 9.7 Hz, 2H), 3.53 (ddd, J= 14.9, 9.7, 5.2 Hz, 2H), 3.49-3.44 (m, 1H), 3.18 (ddt, J = 14.2, 9.4,4.9 Hz, 2H), 2.94- 2.87 (m, 1H), 2.28 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H).LCMS (m/z) (M + H) = 541.2, Rt = 1.13 min 277

N-(3-((6aR, 6bR, 9aR, 9bR)-5-ethyl- 6-oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-5- (trifluoromethyl) nicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 9.34 (d, J = 1.8 Hz, 1H), 9.10- 9.03 (m, 1H), 8.66 (s,1H), 8.25 (d, J = 2.2 Hz, 1H), 7.68-7.60 (m, 2H), 7.60-7.56 (m, 1H),7.33 (d, J = 7.9 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 4.16 (dd, J = 15.4,9.7 Hz, 2H), 3.53 (ddd, J = 14.7, 9.7, 5.2 Hz, 2H), 3.47 (dd, J = 9.4,4.3 Hz, 1H), 3.23- 3.14 (m, 2H), 2.94-2.86 (m, 1H), 2.28 (s, 3H), 1.25(t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) = 523.2, Rt = 1.09 min 278

N-(3-(5-(2- hydroxyethyl)-6- oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin 2-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 2.2Hz, 1H), 8.15- 8.09 (m, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.61-7.56 (m,1H), 7.33 (d, J = 7.9 Hz, 1H), 4.44 (t, J = 6.4 Hz, 2H), 4.16 (dd, J =17.5, 9.7 Hz, 2H), 3.81 (t, J = 6.4 Hz, 2H), 3.60-3.44 (m, 3H), 3.21(ddt, J = 14.6, 9.7, 5.1 Hz, 2H), 2.97-2.88 (m, 1H), 2.28 (s, 3H). LCMS(m/z) (M + H) = 539.3, Rt = 1.02 min 279

2-(1,1- difluoroethyl)-N- (3-(5-(2- hydroxyethyl)-6- oxo-5,6,6a,6b,7,9,9a,9b- octahydrofuro[3′,4′: 3,4]cyclobuta[1,2-c][1,8]naphthyridin- 2-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400MHz, Methanol-d4) δ 8.80 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H),8.17 (s, 1H), 7.96 (dd, J = 5.0, 1.4 Hz, 1H), 7.67-7.61 (m, 2H), 7.59(d, J = 1.6 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.44 (t, J = 6.4 Hz, 2H),4.16 (dd, J = 18.2, 9.7 Hz, 2H), 3.81 (t, J = 6.4 Hz, 2H), 3.58-3.44 (m,3H), 3.21 (ddt, J = 18.4, 9.6, 4.9 Hz, 2H), 2.94 (dt, J = 8.7, 4.9 Hz,1H), 2.28 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H). LCMS (m/z) (M + H) =535.4, Rt = 1.00 min 280

3-fluoro-N-(3-(5- (2-hydroxyethyl)-6- oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.65 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.95(t, J = 4.8 Hz, 1H), 7.64-7.54 (m, 3H), 7.33 (d, J = 8.2 Hz, 1H), 4.44(t, J = 6.4 Hz, 2H), 4.16 (dd, J = 18.5, 9.7 Hz, 2H), 3.81 (t, J = 6.4Hz, 2H), 3.59-3.43 (m, 3H), 3.21 (ddd, J = 18.0, 8.5, 5.1 Hz, 2H),2.98-2.90 (m, 1H), 2.27 (s, 3H). LCMS (m/z) (M + H) = 557.4, Rt = 1.05min 281

N-(3-(5-(2- hydroxyethyl)-6- oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)--4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 2.0Hz, 1H), 8.12 (d, J = 4.4 Hz, 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.59 (d, J= 1.6 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 4.44 (t, J = 6.4 Hz, 2H), 4.16(dd, J = 17.6, 9.7 Hz, 2H), 3.81 (t, J = 6.4 Hz, 2H), 3.52 (ddt, J =20.0, 9.5, 4.6 Hz, 3H), 3.21 (ddt, J = 14.3, 9.5, 4.8 Hz, 2H), 2.98-2.86(m, 1H), 2.28 (s, 3H). LCMS (m/z) (M + H) = 539.3, Rt = 1.02 min 283

3-fluoro-N-(3-(5- (2-hydroxyethyl)-6- oxo- 5,6,6a,6b,7,9,9a,9b-octahydrofuro[3′,4′: 3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4-methylphenyl)-2- (trifluoromethyl)-2- isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.65 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.95(t, J = 4.8 Hz, 1H), 7.63-7.53 (m, 3H), 7.33 (d, J = 8.2 Hz, 1H), 4.44(t, J = 6.4 Hz, 2H), 4.16 (dd, J = 18.5, 9.7 Hz, 2H), 3.81 (t, J = 6.4Hz, 2H), 3.60-3.44 (m, 3H), 3.20 (ddd, J = 18.4, 8.6, 5.1 Hz, 2H),2.97-2.87 (m, 1H), 2.27 (s, 3H). LCMS (m/z) (M + H) = 557.4, Rt = 1.05min 284

N-(3-(7-(2- hydroxyethyl)-6- oxo- 1,2,4,5,5a,6,7,11b- octahydrooxepino[4,5- c][1,8]naphthyridin 10-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J = 5.0 Hz,1H), 8.30 (s, 1H), 8.26-8.22 (m, 1H), 8.12 (dd, J = 5.0, 1.3 Hz, 1H),7.77-7.72 (m, 1H), 7.65 (dd, J = 5.6, 2.3 Hz, 2H), 7.38-7.32 (m, 1H),4.53 (dt, J = 13.0, 5.9 Hz, 1H), 4.25 (dt, J = 13.1, 6.5 Hz, 1H), 3.97(ddd, J = 11.6, 6.4, 3.5 Hz, 2H), 3.89-3.73 (m, 4H), 3.04 (ddd, J =14.2, 10.4, 4.3 Hz, 1H), 2.72 (dq, J = 15.5, 3.3 Hz, 1H), 2.67-2.50 (m,2H), 2.29 (s, 3H), 2.12 (dddd, J = 15.7, 11.4, 9.2, 4.4 Hz, 1H),2.03-1.92 (m, 1H). LCMS (m/z) (M + H) = 541.4, Rt = 1.06 min 285

N-(5-(7-(2- hydroxyethyl)-6- oxo- 1,2,4,5,5a,6,7,11b- octahydrooxepino[4,5- c][1,8]naphthyridin- 10-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J =2.4 Hz, 1H), 8.33- 8.28 (m, 2H), 8.24 (d, J = 7.9 Hz, 1H), 8.17 (d, J =2.4 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.82-7.78 (m, 1H), 7.75 (t, J =7.8 Hz, 1H), 4.53 (dt, J = 12.3, 6.0 Hz, 1H), 4.25 (dt, J = 13.1, 6.5Hz, 1H), 3.97 (dq, J = 11.7, 4.2 Hz, 2H), 3.89-3.74 (m, 4H), 3.05 (ddd,J = 14.2, 10.4, 4.2 Hz, 1H), 2.72 (dq, J = 15.5, 3.3 Hz, 1H), 2.68-2.53(m, 2H), 2.51 (s, 3H), 2.12 (dddd, J = 15.6, 11.3, 9.2, 4.4 Hz, 1H),1.99 (dtd, J = 14.0, 10.7, 3.2 Hz, 1H). LCMS (m/z) (M + H) = 541.4, Rt =0.91 min 286

2-(1,1- difluoroethyl)-N- (3-(7-(2- hydroxyethyl)-6- oxo-1,2,4,5,5a,6,7,11b- octahydrooxepino [4,5- c][1,8]naphthyridin-10-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.80 (d, J = 4.9 Hz, 1H), 8.28- 8.21 (m, 1H), 8.18 (s, 1H), 8.00- 7.93(m, 1H), 7.73 (s, 1H), 7.65 (dd, J = 5.6, 2.3 Hz, 2H), 7.37-7.28 (m,1H), 4.59-4.47 (m, 1H), 4.24 (dt, J = 13.1, 6.5 Hz, 1H), 3.97 (dq, J =10.8, 3.6 Hz, 2H), 3.90-3.70 (m, 4H), 3.09-2.99 (m, 1H), 2.72 (dq, J =15.5, 3.3 Hz, 1H), 2.66-2.51 (m, 2H), 2.29 (s, 3H), 2.16-2.09 (m, 1H),2.08-1.93 (m, 4H). LCMS (m/z) (M + H) = 537.4, Rt = 1.03 min 287

2-(1,1- difluoroethyl)-N- (3-((4aS,10bR)-6- (2-hydroxy-2-methylpropyl)-5- oxo-2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4-c][1,8]naphthyridin- 9-yl)-4- methylphenyl) isonicotinamide 1H NMR (400MHz, Methanol-d4) δ 8.83-8.78 (m, 1H), 8.24 (d, J = 1.3 Hz, 1H),8.20-8.16 (m, 1H), 7.96 (dd, J = 5.0, 1.4 Hz, 1H), 7.70- 7.63 (m, 3H),7.34 (d, J = 8.1 Hz, 1H), 4.67 (d, J = 14.2 Hz, 1H), 4.40 (dd, J = 11.7,4.5 Hz, 1H), 4.14 (dd, J = 11.6, 3.8 Hz, 1H), 3.91 (d, J = 14.2 Hz, 1H),3.64-3.49 (m, 2H), 3.05 (s, 1H), 2.57 (ddd, J = 14.6, 10.5, 4.5 Hz, 1H),2.39-2.31 (m, 1H), 2.29 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H), 1.75 (qd, J= 12.4, 4.6 Hz, 1H), 1.26 (s, 3H), 1.14 (s, 3H). LCMS (m/z) (M + H) =551.2, Rt = 1.04 min 288

(R)-N-(3-(7-(2- hydroxy-2- methylpropyl)-6- oxo-2,4,4a,5,6,7-hexahydro-1H- [1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J = 1.9Hz, 1H), 8.14- 8.09 (m, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.65 (dd, J =8.3, 2.3 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H),4.36 (d, J = 14.0 Hz, 1H), 3.94 (t, J = 11.7 Hz, 2H), 3.87 (d, J = 9.3Hz, 1H), 3.67 (q, J = 10.9 Hz, 2H), 3.41 (s, 1H), 3.01 (d, J = 10.9 Hz,1H), 2.83 (dd, J = 13.3, 7.5 Hz, 1H), 2.30 (s, 3H), 2.22 (d, J = 13.7Hz, 1H), 1.20 (d, J = 3.8 Hz, 3H), 1.14 (s, 3H). LCMS (m/z) (M + H) =570.2, Rt = 0.99 min. 289

(R)-2-(1,1- difluoroethyl)-N- (3-(7-(2-hydroxy-2- methylpropyl)-6-oxo-2,4,4a,5,6,7- hexahydro-1H- [1,4]oxazino[4,3- d]pyrido[2,3-b][1,4]diazepin-10- yl)-4- methylphenyl) isonicotinamide ¹H NMR (400MHz, Methanol-d4) δ 8.83-8.77 (m, 1H), 8.17 (d, J = 2.0 Hz, 2H), 7.96(dd, J = 5.0, 1.4 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 8.3,2.3 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 4.36(d, J = 14.0 Hz, 1H), 3.94 (t, J = 12.1 Hz, 2H), 3.87 (d, J = 9.2 Hz,1H), 3.67 (q, J = 11.0 Hz, 2H), 3.42 (s, 1H), 3.01 (d, J = 10.9 Hz, 1H),2.83 (dd, J = 13.4, 7.5 Hz, 1H), 2.30 (s, 3H), 2.22 (d, J = 13.7 Hz,1H), 2.03 (t, J = 18.7 Hz, 3H), 1.20 (s, 3H), 1.14 (s, 3H). LCMS (m/z)(M + H) = 566.2, Rt = 0.96 min 290

(R)-3-fluoro-N-(3- (7-(2-hydroxy-2- methylpropyl)-6- oxo-2,4,4a,5,6,7-hexahydro-1H- [1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d4) δ 8.65 (d, J = 4.7 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.96(t, J = 4.8 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 9.2, 2.0Hz, 2H), 7.36 (d, J = 8.3 Hz, 1H), 4.64 (s, 1H), 4.35 (d, J = 14.0 Hz,1H), 3.94 (t, J = 11.0 Hz, 2H), 3.87 (d, J = 9.4 Hz, 1H), 3.67 (q, J =11.0 Hz, 2H), 3.42 (s, 1H), 3.36 (s, 1H), 3.01 (d, J = 10.9 Hz, 1H),2.83 (dd, J = 13.3, 7.5 Hz, 1H), 2.30 (s, 3H), 2.22 (d, J = 13.8 Hz,1H), 1.20 (s, 3H), 1.14 (s, 3H). LCMS (m/z) (M + H) = 588.3, Rt = 1.01min. 291

N-(3-((4aR, 10bR)- 6-ethyl- 2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4-c][1,8]naphthyridin- 9-yl)-4- methylpheny)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89 (d, J = 5.05 Hz, 1H), 8.29 (s, 1 H), 8.11 (dd, J = 5.05, 1.26 Hz, 1 H), 7.83 (d, J = 1.52Hz, 1 H), 7.60 (dd, J = 8.08, 2.27 Hz, 1 H), 7.55 (d, J = 2.27 Hz, 1 H),7.27 (dt, J = 3.79, 2.15 Hz, 2 H), 4.11 (td, J = 11.87, 3.79 Hz, 2 H),3.73 (dq, J = 13.96, 7.05 Hz, 1 H), 3.51-3.64 (m, 2 H), 3.30 (m, 1 H),3.19 (dt, J = 19.01, 11.21 Hz, 2 H), 2.59 (td, J = 11.56, 4.17 Hz, 1 H),2.27 (s, 3 H), 2.16- 2.25 (m, 1 H), 1.78 (qt, J = 11.22, 4.26 Hz, 1 H),1.55 (qd, J = 12.29, 4.55 Hz, 1 H), 1.19 (t, J = 7.07 Hz, 3 H). LCMS(m/z) (M + H) = 498.2, Rt = 0.99 min. 292

2-(1,1- difluoroethyl)-N- (3-((4aR, 10bR)-6- ethyl- 2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 5.05 Hz, 1H), 8.17 (d, J = 0.76 Hz, 1 H), 7.90-7.99 (m, 1 H), 7.83 (d, J = 1.52Hz, 1 H), 7.59 (dd, J = 8.08, 2.27 Hz, 1 H), 7.55 (d, J = 2.27 Hz, 1 H),7.21-7.32 (m, 2 H), 4.04-4.19 (m, 2 H), 3.72 (sxt, J = 7.02 Hz, 1 H),3.53-3.64 (m, 2 H), 3.32-3.34 (m, 1 H), 3.19 (dt, J = 19.14, 11.15 Hz, 2H), 2.59 (td, J = 11.37, 3.79 Hz, 1 H), 2.27 (s, 3 H), 2.19-2.25 (m, 1H), 1.93-2.11 (m, 3 H), 1.78 (qt, J = 11.18, 4.33 Hz, 1 H), 1.55 (qd, J= 12.34, 4.67 Hz, 1 H), 1.19 (t, J = 6.95 Hz, 3 H). LCMS (m/z) (M + H) =494.3, Rt = 1.03 min. 293

N-(3-((4aR, 10bR)- 6-ethyl- 2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4-c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-3- fluoro-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.63(d, J = 4.55 Hz, 1 H), 7.94 (t, J = 4.80 Hz, 1 H), 7.82 (dd, J = 2.40,0.88 Hz, 1 H), 7.55 (dd, J = 8.08, 2.27 Hz, 1 H), 7.51 (d, J = 2.27 Hz,1 H), 7.24-7.29 (m, 2 H), 4.10 (td, J = 11.94, 3.92 Hz, 2 H), 3.72 (dq,J = 14.12, 7.00 Hz, 1 H), 3.52-3.64 (m, 2 H), 3.28 (d, J = 4.29 Hz, 1H), 3.18 (dt, J = 18.57, 11.31 Hz, 2 H), 2.58 (td, J = 11.37, 3.79 Hz, 1H), 2.27 (s, 3 H), 2.21-2.25 (m, 1 H), 1.70-1.85 (m, 1 H), 1.55 (qd, J =12.29, 4.55 Hz, 1 H), 1.13-1.24 (m, 3 H). LCMS (m/z) (M + H) = 516.4, Rt= 0.96 min. 294

N-(5-((4aR, 10bR)- 6-ethyl- 2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4-c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-2-fluoro-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.72 (d, J =2.53 Hz, 1 H), 7.94- 8.05 (m, 2 H), 7.82-7.93 (m, 2 H), 7.49 (t, J =7.71 Hz, 1 H), 7.24-7.35 (m, 1 H), 4.03-4.17 (m, 2 H), 3.73 (dq, J =14.02, 7.03 Hz, 1 H), 3.51- 3.65 (m, 2 H), 3.31-3.34 (m, 1 H), 3.19 (dt,J = 14.97, 11.34 Hz, 2 H), 2.59 (td, J = 11.37, 3.54 Hz, 1 H), 2.43-2.53(m, 3 H), 2.21-2.37 (m, 1 H), 1.68-1.86 (m, 1 H), 1.56 (qd, J = 12.29,4.55 Hz, 1 H), 1.15-1.23 (m, 3 H). LCMS (m/z) (M + H) = 515.2, Rt = 0.86min. 295

N-(5-((4aR, 10bR)- 6-ethyl- 2,4,4a,5,6,10b- hexahydro-1H- pyrano[3,4-c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3- (trifluoromethyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.72-8.80 (m, 1 H), 8.29 (s, 1H), 8.23 (br d, J = 7.83 Hz, 1 H), 8.05 (d, J = 2.27 Hz, 1 H), 7.86-7.95(m, 2 H), 7.66-7.78 (m, 1 H), 7.31 (d, J = 1.52 Hz, 1 H), 4.04-4.18 (m,2 H), 3.66-3.80 (m, 1 H), 3.52-3.65 (m, 2 H), 3.32-3.36 (m, 1 H), 3.08-3.26 (m, 2 H), 2.53-2.65 (m, 1 H), 2.43-2.53 (m, 3 H), 2.21-2.36 (m, 1H), 1.70-1.87 (m, 1 H), 1.56 (qd, J = 12.21, 4.29 Hz, 1H), 1.13- 1.24(m, 3 H). LCMS (m/z) (M + H) = 497.1, Rt = 0.90 min. 296

N-(5-((4aS,11bR- cis)-7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm8.77 (br s, 1 H), 8.25-8.60 (m, 3 H), 8.22 (s, 1 H), 8.18 (br d, J =7.78 Hz, 1 H), 7.89 (d, J = 7.78 Hz, 1 H), 7.71 (t, J = 7.78 Hz, 1 H),7.67 (d, J = 2.01 Hz, 1 H), 4.86 (ddd, J = 7.53, 5.52, 4.02 Hz, 1 H),4.04-4.24 (m, 2 H), 3.82- 3.98 (m, 3 H), 3.46-3.60 (m, 2 H), 2.62 (s, 3H), 2.26-2.39 (m, 1 H), 2.04-2.22 (m, 1 H), 1.36 (t, J = 7.03 Hz, 3 H).LCMS (m/z) (M + H) = 527.1, Rt = 1.07 min. 297

N-(3-((4aS,11bR- cis)7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm8.96 (d, J = 5.05 Hz, 1 H), 8.42 (d, J = 2.02 Hz, 1 H), 8.31 (s, 1 H),8.19 (s, 1 H), 8.02 (d, J = 4.29 Hz, 1 H), 7.69-7.78 (m, 2 H), 7.66 (brd, J = 8.34 Hz, 1 H), 7.39 (d, J = 8.34 Hz, 1 H), 4.80- 4.92 (m, 1 H),4.09-4.30 (m, 2 H), 3.81-3.94 (m, 3 H), 3.43-3.54 (m, 2 H), 2.26-2.38(m, 4 H), 2.09- 2.22 (m, 1 H), 1.34 (t, J = 7.07 Hz, 3 H). LCMS (m/z)(M + H) = 527.2, Rt = 1.17 min. 298

N-(5-((4aS,11bR- cis)-7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.84 (br s, 1 H), 8.32-8.68 (m, 3 H), 8.17- 8.31 (m, 2 H), 7.89 (d, J =7.83 Hz, 1 H), 7.63-7.77 (m, 2 H), 4.86 (ddd, J = 7.52, 5.49, 3.92 Hz, 1H), 4.03- 4.25 (m, 2 H), 3.80-3.96 (m, 3 H), 3.49-3.59 (m, 2 H), 2.64(s, 3 H), 2.26-2.41 (m, 1 H), 2.05-2.20 (m, 1 H), 1.36 (t, J = 7.07 Hz,3 H). LCMS (m/z) (M + H) = 527.1, Rt = 1.07 min. 299

N-(3-((4aS,11bR- cis)-7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4- methylphenyl)-3-fluoro-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.73 (d, J = 4.80 Hz, 1 H), 8.41 (d, J = 2.27 Hz, 1H), 8.36 (br d, J = 12.38 Hz, 1 H), 8.27 (t, J = 5.18 Hz, 1 H), 7.68 (d,J = 2.27 Hz, 1 H), 7.66 (d, J = 1.77 Hz, 1 H), 7.57 (dd, J = 8.34, 2.27Hz, 1 H), 7.39 (d, J = 8.34 Hz, 1 H), 4.87 (ddd, J = 8.02, 5.75, 4.17Hz, 1 H), 4.02-4.26 (m, 2 H), 3.82-3.95 (m, 3 H), 3.45-3.55 (m, 2 H),2.27- 2.39 (m, 4 H), 2.08-2.21 (m, 1 H), 1.35 (t, J = 7.07 Hz, 3 H).LCMS (m/z) (M + H) = 545.2, Rt = 1.21 min. 300

N-(5-((4aS,11bR- cis)-7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-6- methylpyridin-3-yl)-2-fluoro-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.72 (br s, 1 H), 8.59 (br s, 1 H), 8.44 (d, J =2.02 Hz, 1 H), 8.24-8.42 (m, 2 H), 7.88 (t, J = 6.82 Hz, 1 H), 7.66 (d,J = 1.52 Hz, 1 H), 7.49 (t, J = 7.71 Hz, 1 H), 4.78-4.92 (m, 1 H), 4.03-4.25 (m, 2 H), 3.80-3.98 (m, 3 H), 3.46-3.61 (m, 2 H), 2.60 (s, 3 H),2.27-2.39 (m, 1 H), 2.07-2.23 (m, 1 H), 1.36 (t, J = 7.07 Hz, 3 H). LCMS(m/z) (M + H) = 545.2, Rt = 1.04 min. 301

N-(3-((4aS,11bR- cis)-7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO-d6) δppm 10.89 (s, 1 H), 9.92 (d, J = 2.02 Hz, 1 H), 8.68 (d, J = 2.02 Hz, 1H), 8.40 (d, J = 2.02 Hz, 1 H), 7.86 (d, J = 2.02 Hz, 1 H), 7.66-7.79(m, 2 H), 7.40 (d, J = 8.08 Hz, 1 H), 4.73- 4.84 (m, 1 H), 3.90-4.03 (m,2 H), 3.80-3.90 (m, 1 H), 3.60-3.72 (m, 2 H), 3.48-3.60 (m, 2 H), 2.29(s, 3 H), 2.15 (ddt, J = 10.67, 7.07, 3.63, 3.63 Hz, 1 H), 1.88-2.00 (m,1 H), 1.26 (t, J = 6.95 Hz, 3 H). LCMS (m/z) (M + H) = 528.1, Rt = 1.10min. 302

2-(1,1- difluoroethyl)-N- (3-((4aS,11bR-cis)- 7-ethyl-6-oxo-2,4,4a,6,7,11b- hexahydro-1H- pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin-10-yl)- methylphenyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm10.66 (s, 1 H), 8.89 (d, J = 5.05 Hz, 1 H), 8.40 (d, J = 2.27 Hz, 1 H),8.19 (s, 1 H), 8.03 (d, J = 5.05 Hz, 1 H), 7.86 (d, J = 2.02 Hz, 1 H),7.71- 7.79 (m, 2 H), 7.37 (d, J = 8.34 Hz, 1 H), 4.73-4.82 (m, 1 H),3.96 (tt, J = 13.58, 6.76 Hz, 2 H), 3.80-3.89 (m, 1 H), 3.60-3.72 (m, 2H), 3.49- 3.59 (m, 2 H), 2.28 (s, 3 H), 2.11- 2.22 (m, 1 H), 2.05 (t, J= 19.07 Hz, 3 H), 1.97 (br s, 1 H), 1.25 (t, J = 6.95 Hz, 3 H). LCMS(m/z) (M + H) = 523.1, Rt = 1.15 min. 303

N-(3-((4aS,10bR)- 6-ethyl-5-oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (s,1 H), 9.38 (d, J = 1.77 Hz, 1 H), 9.19 (d, J = 1.26 Hz, 1 H), 8.69 (s, 1H), 8.29 (d, J = 1.52 Hz, 1 H), 7.68-7.75 (m, 2 H), 7.61 (s, 1 H), 7.36(d, J = 8.08 Hz, 1 H), 4.22- 4.30 (m, 1 H), 4.12-4.21 (m, 1 H),3.95-4.08 (m, 2 H), 3.44 (q, J = 10.86 Hz, 2 H), 2.92-3.04 (m, 1 H),2.52-2.57 (m, 1 H), 2.25-2.36 (m, 4 H), 1.59 (qd, J = 12.29, 4.29 Hz, 1H), 1.18 (t, J = 6.95 Hz, 3 H). LCMS (m/z) (M + H) = 511.1, Rt = 1.21min. 304

N-(3-((4aR, 11bR)- 7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4- methylphenyl)-3-fluoro-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.73 (d, J = 4.80 Hz, 1 H), 8.43 (d, J = 2.27 Hz, 1H), 8.37 (br d, J = 12.38 Hz, 1 H), 8.27 (t, J = 5.18 Hz, 1 H), 7.66 (d,J = 2.27 Hz, 1 H), 7.58 (dd, J = 8.21, 2.40 Hz, 1 H), 7.53 (d, J = 1.77Hz, 1 H), 7.39 (d, J = 8.34 Hz, 1 H), 3.99- 4.33 (m, 5 H), 3.50-3.66 (m,2 H), 2.91-3.09 (m, 1 H), 2.33 (s, 3 H), 2.03-2.19 (m, 2 H), 1.35 (t, J= 6.95 Hz, 3 H). LCMS (m/z) (M + H) = 545.2, Rt = 1.11 min. 305

N-(3-((4aR,11bR)- 7-ethyl-6-oxo- 2,4,4a,6,7,11b- hexahydro-1H-pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm8.96 (d, J = 4.80 Hz, 1 H), 8.42 (d, J = 2.27 Hz, 1 H), 8.14 (s, 1 H),7.96 (br d, J = 3.28 Hz, 2 H), 7.65 (s, 1 H), 7.59 (br d, J = 8.08 Hz, 1H), 7.51 (d, J = 1.77 Hz, 1 H), 7.39 (d, J = 8.08 Hz, 1 H), 3.98-4.30(m, 5 H), 3.51- 3.66 (m, 2 H), 2.94-3.08 (m, 1 H), 2.33 (s, 3 H),2.04-2.13 (m, 2 H), 1.34 (t, J = 6.95 Hz, 3 H). LCMS (m/z) (M + H) =527.2, Rt = 1.10 min. 306

N-(3-((4aS,10bR)- 6-(2-hydroxyethyl)- 5-oxo- 2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, DMSO-d6) ppm 10.65 (s, 1H), 9.38 (d, J = 1.77 Hz, 1 H), 9.19 (d, J = 1.01 Hz, 1 H), 8.69 (s, 1H), 8.28 (d, J = 1.52 Hz, 1 H), 7.69-7.75 (m, 2 H), 7.61 (s, 1 H), 7.36(d, J = 8.08 Hz, 1 H), 4.78 (t, J = 5.81 Hz, 1 H), 4.21-4.36 (m, 2 H),3.97-4.12 (m, 2 H), 3.36- 3.68 (m, 4 H), 2.90-3.07 (m, 1 H), 2.52-2.58(m, 1 H), 2.30-2.37 (m, 1 H), 2.27 (s, 3 H), 1.59 (qd, J = 12.25, 4.42Hz, 1 H). LCMS (m/z) (M + H) = 527.1, Rt = 1.03 min. 307

3-fluoro-N-(3 - ((4aS, 10bR)-6-(2- hydroxyethyl)-5- oxo-2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm10.75-11.01 (m, 1 H), 8.76 (d, J = 4.77 Hz, 1 H), 8.27 (d, J = 1.51 Hz,1 H), 8.10 (t, J = 4.77 Hz, 1 H), 7.57- 7.66 (m, 3 H), 7.36 (d, J = 8.03Hz, 1 H), 4.45-5.10 (m, 1 H), 4.19- 4.36 (m, 2 H), 3.94-4.12 (m, 2 H),3.41-3.64 (m, 4 H), 2.92-3.06 (m, 1 H), 2.52-2.58 (m, 1 H), 2.29- 2.38(m, 1 H), 2.26 (s, 3 H), 1.58 (qd, J = 12.21, 4.52 Hz, 1 H). LCMS (m/z)(M + H) = 545.2, Rt = 1.01 min. 308

(R)-2-(1,1- difluoroethyl)-3- fluoro-N-(3-(7-(2- hydroxyethyl)-6-oxo-2,4,4a,5,6,7- hexahydro-1H- [1,4]oxazino[4,3- d]pyrido[2,3-b][1,4]diazepin-10- yl)-4- methylphenyl) isonicotinamide ¹H NMR (400MHz, METHANOL- d4) δ ppm 8.55 (d, J = 4.80 Hz, 1 H), 8.18 (d, J = 1.77Hz, 1 H), 7.80 (t, J = 4.80 Hz, 1 H), 7.68 (d, J = 2.27 Hz, 1 H),7.54-7.65 (m, 2 H), 7.36 (d, J = 8.08 Hz, 1 H), 4.25-4.41 (m, 1 H),3.79-3.98 (m, 4 H), 3.61-3.76 (m, 3 H), 3.44 (br d, J = 8.59 Hz, 1 H),3.32-3.37 (m, 1 H), 3.01 (br d, J = 11.37 Hz, 1 H), 2.79 (dd, J = 13.77,7.45 Hz, 1 H), 2.31 (s, 3 H), 2.22 (d, J = 13.64 Hz, 1 H), 2.08 (t, J =18.95 Hz, 3 H). LCMS (m/z) (M + H) = 556.1, Rt = 0.94 min. 309

N-(5-((4aR, 10bS)- 6-ethyl-5-oxo- 1,4,4a,5,6,10b- hexahydro-2H-pyrano[3,4 - c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide 1H NMR (400 MHz, Methanol-d4) δ 8.84 (d, J =2.5 Hz, 1H), 8.33 (dd, J = 2.2, 0.8 Hz, 1H), 8.31 (s, 1H), 8.25 (d, J =7.9 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.76(t, J =+) 7.9 Hz, 1H), 7.72- 7.67 (m, 1H), 4.42 (dd, J = 11.7, 4.5 Hz,1H), 4.31 (dq, J = 13.9, 6.9 Hz, 1H), 4.13 (dd, J = 13.1, 7.0 Hz, 2H),3.64-3.43 (m, 3H), 3.05-2.91 (m, 1H), 2.52 (s, 3H), 2.34 (d, J = 9.6 Hz,1H), 1.75 (qd, J = 12.4, 4.6 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H). LCMS(m/z) (M + H) = 511.1989, Rt = 3.07 min 310

N-(5-((4aR, 10bS)- 6-ethyl-5-oxo- 1,4,4a,5,6,10b- hexahydro-2H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-2-(2-fluoropropan-2- yl)isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.85(d, J = 2.5 Hz, 1H), 8.72 (d, J = 5.1 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H),8.18 (d, J = 2.5 Hz, 1H), 8.10 (s, 1H), 7.80 (dd, J = 5.1, 1.7 Hz, 1H),7.71-7.64 (m, 1H), 4.41 (dd, J = 11.7, 4.5 Hz, 1H), 4.31 (dq, J = 13.8,7.0 Hz, 1H), 4.13 (dq, J = 13.8, 6.9 Hz, 2H), 3.65-3.44 (m, 2H), 2.99(s, 1H), 2.52 (s, 5H), 2.39- 2.26 (m, 1H), 1.73 (d, J = 21.9 Hz, 6H),1.26 (q, J = 7.2 Hz, 3H). LCMS (m/z) (M + H) = 504.2410, Rt = 2.70 min311

N-(3-((4aS, 10bR)- 6-ethyl-5-oxo- 1,4,4a,5,6,10b- hexahydro-2H-pyrano[3,4 - c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.90(t, J = 4.9 Hz, 1H), 8.30 (s, 1H), 8.26 (dd, J = 2.1, 0.8 Hz, 1H), 8.12(dd, J = 5.0, 1.2 Hz, 1H), 7.69- 7.60 (m, 3H), 7.38-7.31 (m, 1H), 4.41(dd, J =+) 11.6, 4.5 Hz, 1H), 4.30 (dq, J = 13.9, 7.0 Hz, 1H), 4.12 (dd,J = 13.1, 7.0 Hz, 2H), 3.64-3.46 (m, 2H), 3.02-2.91 (m, 1H), 2.48 (dtd,J = 16.1, 11.5, 11.0, 5.4 Hz, 1H), 1.73 (qd, J = 12.5, 4.6 Hz, 2H),1.49-1.41 (m, 3H), 1.25 (d, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) =511.1971, Rt = 3.88 min 312

N-(5-((4aS, 10bR)- 6-ethyl-5-oxo- 1,4,4a,5,6,10b- hexahydro-2H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide 1H NMR (400 MH, Methanol-d4) δ 8.84 (d, J =2.5 Hz, 1H), 8.35- 8.29 (m, 2H), 8.25 (d, J = 7.8 Hz, 1H), 8.18 (d, J =2.5 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.70(dd, J = 2.1, 1.4 Hz, 1H), 4.42 (dd, J = 11.6, 4.5 Hz, 1H), 4.31 (dq, J= 13.9, 7.0 Hz, 1H), 4.13 (dq, J = 13.9, 7.0 Hz, 2H), 3.63- 3.46 (m,2H), 3.04-2.94 (m, 1H), 2.56-2.44 (m, 4H), 2.34 (d, J = 9.4 Hz, 1H),1.80-1.69 (m, 1H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (m/z) (M + H) =511.1969, Rt = 3.07 min 313

N-(5-((4aS, 10bR)- 6-ethyl-5-oxo- 1,4,4a,5,6,10b- hexahydro-2H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-2-(2-fluoropropan-2- yl)isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.85(d, J = 2.4 Hz, 1H), 8.72 (d, J = 5.1 Hz, 1H), 8.34-8.29 (m, 1H), 8.18(d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.80 (dd, J = 5.1, 1.6 Hz, 1H), 7.70(s, 1H), 4.41 (dd, J = 11.6, 4.4 Hz, 1H), 4.30 (dt, J = 13.8, 6.9 Hz,1H), 4.12 (dt, J = 13.8, 7.1 Hz, 2H), 3.55 (dt, J = 18.8, 11.3 Hz, 3H),2.98 (s, 1H), 2.59-2.43 (m, 5H), 1.73 (d, J = 21.9 Hz, 6H), 1.26 (q, J =7.1 Hz, 3H) LCMS (m/z) (M + H) = 504.2417, Rt = 2.70 min 314

N-(3-(8-ethyl-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.91(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.21-8.07 (m, 2H), 7.75-7.61 (m, 3H),7.36 (d, J = 8.3 Hz, 1H), 4.06 (qd, J = 6.9, 2.7 Hz, 2H), 3.94 (dddd, J= 13.8, 12.5, 7.6, 3.1 Hz, 3H), 3.87-3.74 (m, 2H), 3.56-3.35 (m, 2H),2.64 (dd, J = 13.2, 5.4 Hz, 1H), 2.40-2.24 (m, 4H), 2.23-2.05 (m, 1H),1.93-1.83 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 540.3,Rt = 1.16 min 315

N-(5-(8-ethyl-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.84(d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 8.29-8.17 (m, 3H), 7.92 (d, J = 7.8Hz, 1H), 7.81-7.62 (m, 2H), 4.07 (qd, J = 6.8, 2.0 Hz, 2H), 4.01- 3.90(m, 3H), 3.90-3.73 (m, 2H), 3.47 (dt, J = 8.4, 4.0 Hz, 2H), 2.66 (dd, J= 13.3, 5.3 Hz, 1H), 2.54 (s, 3H), 2.35 (dd, J = 13.3, 6.5 Hz, 1H), 2.14(ddd, J = 15.1, 8.2, 3.2 Hz, 1H), 2.00-1.85 (m, 1H), 1.19 (d, J = 7.1Hz, 3H). LCMS (m/z) (M + H) = 540.3, Rt = 0.98 min 316

N-(3-(8-ethyl-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.12 (dd, J = 7.1, 1.6 Hz, 2H),7.76-7.58 (m, 3H), 7.35 (d, J = 8.3 Hz, 1H), 4.06 (qd, J = 6.9, 2.6 Hz,2H), 4.00-3.72 (m, 5H), 3.51-3.36 (m, 2H), 2.63 (dd, J = 13.2, 5.4 Hz,1H), 2.45-2.25 (m, 4H), 2.24-2.04 (m, 1H), 1.90 (dd, J = 15.1, 2.4 Hz,1H), 1.18 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 540.3, Rt = 1.16 min317

N-(5-(8-ethyl-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.84(d, J = 2.5 Hz, 1H), 8.31 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.21 (d, J= 2.5 Hz, 1H), 8.19 (d, J= 2.0 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75(t, J = 7.8 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 4.07 (qd, J = 6.9, 2.3Hz, 2H), 4.02-3.89 (m, 3H), 3.89- 3.72 (m, 2H), 3.47 (dt, J = 8.2, 3.9Hz, 2H), 2.66 (dd, J = 13.3, 5.4 Hz, 1H), 2.54 (s, 3H), 2.35 (dd, J =13.3, 6.5 Hz, 1H), 2.16 (ddd, J = 14.2, 10.0, 4.8 Hz, 1H), 1.97-1.87 (m,1H), 1.22-1.17 (m, 3H). LCMS (m/z) (M + H) = 540.2, Rt = 0.98 min 318

N-(3-(8-(2- hydroxyethyl)-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.12 (dd, J = 4.2, 1.6 Hz, 2H), 7.71(d, J = 2.3 Hz, 1H), 7.69-7.62 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 4.12(t, J = 5.9 Hz, 2H), 4.02-3.89 (m, 3H), 3.79 (dddd, J = 17.0, 13.2, 9.4,5.0 Hz, 4H), 3.50-3.40 (m, 2H), 2.69 (dd, J = 13.3, 5.3 Hz, 1H), 2.38(dd, J = 13.3, 6.6 Hz, 1H), 2.31 (s, 3H), 2.23-2.04 (m, 1H), 1.91 (dq, J= 15.0, 3.5 Hz, 1H). LCMS (m/z) (M + H) = 556.3, Rt = 1.02 min 319

N-(5-(8-(2- hydroxyethyl)-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide 1H NMR (400 MHz, Methanol-d4) δ 8.84(d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.26-8.20 (m, 2H), 8.17 (d, J = 2.0Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.78-7.69 (m, 2H), 4.14 (td, J = 5.9,1.5 Hz, 2H), 4.02-3.89 (m, 3H), 3.89-3.74 (m, 4H), 3.54-3.40 (m, 2H),2.71 (dd, J = 13.3, 5.2 Hz, 1H), 2.53 (s, 3H), 2.40 (dd, J = 13.4, 6.5Hz, 1H), 2.16 (dd, J = 9.8, 4.5 Hz, 1H), 1.93 (dd, J = 15.1, 2.4 Hz,1H). LCMS (m/z) (M + H) = 556.3, Rt = 0.85 min 320

N-(3-(8-(2- hydroxyethyl)-7- oxo- 1,2,4,5,5a,6,7,8- octahydropyrido[3′,2′:2,3][1,4]diazepino [1,7- d][1,4]oxazepin- 11-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.91(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.14-8.09 (m, 2H), 7.72 (d, J = 2.2Hz, 1H), 7.67 (dd, J = 7.4, 1.8 Hz, 2H), 7.36 (d, J = 8.3 Hz, 1H), 4.12(t, J = 5.9 Hz, 2H), 3.95 (dp, J = 12.8, 4.4, 3.9 Hz, 3H), 3.89-3.69 (m,4H), 3.47 (dt, J = 7.9, 3.8 Hz, 2H), 2.69 (dd, J = 13.3, 5.3 Hz, 1H),2.38 (dd, J = 13.3, 6.6 Hz, 1H), 2.32 (s, 3H), 2.14 (dq, J = 9.6, 5.6,5.1 Hz, 2H), 1.96-1.87 (m, 1H). LCMS (m/z) (M + H) = 556.2, Rt = 1.02min 322

(R)-3-fluoro-N-(3- (7-(2- hydroxyethyl)-6- oxo-2,4,4a,5,6,7-hexahydro-1H- [1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide 1H NMR (400 MHz,DMSO-d6) δ 10.90 (s, 1H), 8.76 (d, J = 4.7 Hz, 1H), 8.17 (d, J = 2.0 Hz,1H), 8.11 (t, J = 4.8 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.62 (dd, J =8.2, 2.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H),4.87 (t, J = 5.5 Hz, 1H), 4.12 (s, 1H), 3.85 (t, J = 11.8 Hz, 2H),3.78-3.60 (m, 2H), 3.48 (dt, J = 19.1, 11.0 Hz, 3H), 3.34-3.21 (m, 2H),2.94 (d, J = 10.8 Hz, 1H), 2.70 (dd, J = 13.4, 7.3 Hz, 1H), 2.27 (s,3H), 2.18-2.04 (m, 1H). LCMS (m/z) (M + H) = 560.1838, Rt = 3.09 min 323

(R)-N-(3-(7-(2- hydroxyethyl)-6- oxo-2,4,4a,5,6,7- hexahydro-1H-[1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-6- (trifluoromethyl) pyridazine-4- carboxamide 1H NMR (400MHz, Methanol-d4) δ 9.87 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H),8.18 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.3,2.3 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.35(d, J = 8.0 Hz, 1H), 3.98- 3.78 (m, 5H), 3.75-3.60 (m, 3H), 3.00 (d, J =11.1 Hz, 1H), 2.79 (dd, J = 13.7, 7.5 Hz, 1H), 2.32 (s, 3H), 2.22 (d, J= 13.7 Hz, 1H), 1.45 (s, 1H). LCMS (m/z) (M + H) = 543.19, Rt = 0.93 min324

(S)-N-(3-(7-(2- hydroxyethyl)-6- oxo-2,4,4a,5,6,7- hexahydro-1H-[1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-6- (trifluoromethyl) pyridazine-4- carboxamide 1H NMR (400MHz, Methanol-d4) δ 9.87 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H),8.18 (d, J = 2.0 Hz' 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.3,2.3 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.35(d, J = 8.0 Hz, 1H), 3.98- 3.78 (m, 5H), 3.75-3.60 (m, 3H), 3.00 (d, J =11.1 Hz, 1H), 2.79 (dd, J = 13.7, 7.5 Hz, 1H), 2.32 (s, 3H), 2.22 (d, J= 13.7 Hz, 1H), 1.45 (s, 1H). LCMS (m/z) (M + H) = 543.19, Rt = 0.93 min325

(R)-N-(3-(7-ethyl- 6-oxo-2,4,4a,5,6,7- hexahydro-1H- [1,4]oxazino[4,3-d]pyrido[2,3- b][1,4]diazepin-10- yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz,Methanol-d₄) δ 9.90 (d, J = 1.9 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.21(d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 8.3, 2.3Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 4.14-4.00(m, J = 6.9 Hz, 2H), 3.97 (dd, J = 11.1, 2.1 Hz, 1H), 3.88 (dd, J =10.9, 2.5 Hz, 1H), 3.72- 3.62 (m, 2H), 3.45-3.34 (m, 2H), 3.00 (d, J =11.3 Hz, 1H), 2.77 (dd, J = 13.7, 7.5 Hz, 1H), 2.35 (s, 3H), 2.20 (d, J= 13.7 Hz, 1H), 1.20 (d, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 527.1, Rt= 1.07 min 326

(S)-N-(3-(7-ethyl- 6-oxo-2,4,4a,5,6,7- hexahydro-1H- [1,4]oxazino[4,3-d]pyrido[2,3- b][1,4]diazepin-10- yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz,Methanol-d₄) δ 9.90 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.21(d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 8.3, 2.3Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 4.08 (p, J= 6.5 Hz, 2H), 3.97 (dd, J = 11.2, 2.3 Hz, 1H), 3.88 (dd, J = 11.0, 2.6Hz, 1H), 3.73-3.61 (m, 2H), 3.47-3.34 (m, 2H), 3.00 (d, J = 11.2 Hz,1H), 2.77 (dd, J = 13.7, 7.5 Hz, 1H), 2.35 (s, 3H), 2.20 (d, J = 13.7Hz, 1H), 1.20 (d, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 527.1, Rt = 1.07min 327

(R)-N-(3-(7-ethyl- 6-oxo-2,4,4a,5,6,7- hexahydro-1H- [1,4]oxazino[4,3-d]pyrido[2,3- b][1,4]diazepin-10- yl)-4- methylphenyl)-3- fluoro-2-(trifluoromethyl) isonicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.56(d, J = 4.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.86 (t, J = 4.8 Hz, 1H),7.58 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 8.3, 2.3 Hz, 1H), 7.47 (d, J =2.0 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 3.95 (hept, J = 6.8 Hz, 2H), 3.84(dd, J = 11.1, 2.2 Hz, 1H), 3.76 (dd, J = 11.0, 2.5 Hz, 1H), 3.54 (q, J= 10.0, 9.3 Hz, 2H), 3.30 (t, J = 7.9 Hz, 1H), 2.88 (d, J = 11.3 Hz,1H), 2.65 (dd, J = 13.7, 7.5 Hz, 1H), 2.21 (s, 3H), 2.07 (d, J = 13.6Hz, 1H), 1.08 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 544.4, Rt = 1.16min 328

(R)-N-(3-(7-ethyl- 6-oxo-2,4,4a,5,6,7- hexahydro-1H- [1,4]oxazino[4,3-d]pyrido[2,3- b][1,4]diazepin-10- yl)-4- methylphenyl)-5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, Methanol-d₄) δ 9.25 (d,J = 1.6 Hz, 1H), 8.98 (s, 1H), 8.57 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H),7.63 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.3, 2.2 Hz, 1H), 7.48 (d, J =2.0 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 3.96 (hept, J = 6.8 Hz, 2H), 3.85(d, J = 9.4 Hz, 1H), 3.76 (dd, J = 11.0, 2.4 Hz, 1H), 3.61- 3.50 (m,2H), 3.31 (s, 2H), 2.89 (d, J = 11.4 Hz, 1H), 2.65 (dd, J = 13.6, 7.5Hz, 1H), 2.23 (s, 3H), 2.08 (d, J = 13.7 Hz, 1H), 1.09 (t, J = 7.1 Hz,3H). LCMS (m/z) (M + H) = 526.2, Rt = 1.04 min 329

(R)-N-(3-(7-(2- hydroxyethyl)-6- oxo-2,4,4a,5,6,7- hexahydro-1H-[1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-5- (trifluoromethyl) nicotinamide ¹H NMR (400 MHz,Methanol-d₄) δ 9.37 (d, J = 1.9 Hz, 1H), 9.12-9.08 (m, 1H), 8.69 (s,1H), 8.21 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.68 (dd, J =8.3, 2.3 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H),4.42-4.32 (m, 1H), 4.00-3.94 (m, 1H), 3.93-3.81 (m, 3H), 3.77-3.63 (m,3H), 3.41 (dd, J = 23.6, 5.1 Hz, 2H), 3.03 (d, J = 11.9 Hz, 1H), 2.82(dd, J = 13.7, 7.5 Hz, 1H), 2.34 (s, 3H), 2.24 (d, J = 13.7 Hz, 1H).LCMS (m/z) (M + H) = 542.3, Rt = 0.90 min 330

N-(3-((4,11b-cis)- 7-(2-hydroxyethyl)- 6-oxo- 2,4,4a,6,7,11b-hexahydro-1H- pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d₄) δ 8.92 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.32(s, 1H), 8.14 (dd, J = 5.0, 1.3 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.73(dd, J = 8.2, 2.3 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 8.3Hz, 1H), 4.70-4.61 (m, 2H), 4.30 (q, J = 8.6 Hz, 1H), 4.20 (q, J = 8.3Hz, 1H), 4.07 (dd, J = 11.3, 3.9 Hz, 1H), 3.97-3.88 (m, 2H), 3.76-3.68(m, 1H), 3.62 (td, J = 11.9, 2.0 Hz, 1H), 3.32-3.27 (m, 1H), 2.42 (qd, J= 12.8, 4.6 Hz, 1H), 2.33 (s, 3H), 1.61-1.51 (m, 1H). LCMS (m/z) (M + H)= 543.1857, Rt = 2.77 min 331

3-fluoro-N-(3- ((4,11b-cis)-7-(2- hydroxyethyl)-6- oxo-2,4,4a,6,7,11b-hexahydro-1H- pyrano[4,3- f]pyrido[2,3- d][1,3]oxazepin- 10-yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d₄) δ 8.55 (d, J = 4.7 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.99(d, J = 2.3 Hz, 1H), 7.86 (t, J = 4.8 Hz, 1H), 7.57 (dd, J = 8.2, 2.2Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 4.53 (t, J= 8.1 Hz, 2H), 4.18 (q, J = 8.5 Hz, 1H), 4.08 (q, J = 8.2 Hz, 1H), 3.95(dd, J = 11.3, 3.8 Hz, 1H), 3.86-3.75 (m, 2H), 3.59 (d, J = 11.8 Hz,1H), 3.50 (td, J = 11.9, 1.8 Hz, 1H), 3.22-3.15 (m, 1H), 2.30 (qt, J =12.8, 6.3 Hz, 1H), 2.21 (s, 3H), 1.46 (d, J = 12.7 Hz, 1H). LCMS (m/z)(M + H) = 561.1757, Rt = 2.88 min 332

2-(1,1- difluoroethyl)-N- (3-((4,11b-cis)-7- (2-hydroxyethyl)-6-oxo-2,4,4a,6,7,11b- hexahydro-1H- pyrano[4,3- f]pyrido[2,3-d][1,3]oxazepin- 10-yl)-4- methylphenyl) isonicotinamide 1HNMR: 1H NMR(400 MHz, Methanol-d4) δ 8.71 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 2.3 Hz,1H), 8.09 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 5.1 Hz, 1H),7.62 (dd, J = 8.2, 2.2 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.27 (d, J =8.3 Hz, 1H), 4.59-4.49 (m, 2H), 4.19 (q, J = 8.5 Hz, 1H), 4.09 (q, J =8.2 Hz, 1H), 3.96 (dd, J = 11.2, 3.8 Hz, 1H), 3.88- 3.71 (m, 2H), 3.60(d, J = 11.9 Hz, 1H), 3.51 (td, J = 11.9, 1.9 Hz, 1H), 3.18 (d, J = 3.7Hz, 1H), 2.30 (qd, J = 12.8, 4.6 Hz, 1H), 2.22 (s, 3H), 1.94 (t, J =18.7 Hz, 3H), 1.46 (d, J = 12.9 Hz, 1H). LCMS (m/z) (M + H) = 539.2130,Rt = 2.66 min 333

(R)-N-(3-(7-(2- hydroxyethyl)-6- oxo-2,4,4a,5,6,7- hexahydro-1H-[1,4]oxazino[4,3- d]pyrido[2,3- b][1,4]diazepin-10- yl)-4-methylphenyl)-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz,Methanol-d₄) δ 8.90 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J = 2.0Hz, 1H), 8.12 (dd, J = 5.0, 1.2 Hz, 1H), 7.72 (d, J = 22.2 Hz, 1H), 7.66(dd, J = 8.2, 2.3 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.3Hz, 1H), 4.40-4.29 (m, 1H), 3.94 (dd, J = 11.1, 2.2 Hz, 1H), 3.91-3.79(m, 3H), 3.74- 3.61 (m, 3H), 3.43 (d, J = 7.5 Hz, 2H), 3.01 (d, J = 11.5Hz, 1H), 2.79 (dd, J = 13.8, 7.5 Hz, 1H), 2.31 (s, 3H), 2.22 (d, J =13.8 Hz, 1H). LCMS (m/z) (M + H) = 542.3, Rt = 0.94 min

Synthesis of9-(5-amino-2-methylphenyl)-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(from Peak 1)

A mixture of2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide(1.0 equiv: see Ex. 160) in 1:1 THF/MeOH (0.051 M) and NaOH (1 M aq, 10equiv) was heated to 75° C. and stirred for 4 h. The mixture was pouredonto water and extracted three times with ethyl acetate. LCMS Thecombined organics were washed with brine, dried over magnesium sulfate,filtered, and concentrated to9-(5-amino-2-methylphenyl)-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olwhich was used without further purification. LCMS (m/z) (M+H)=340.3,Rt=0.57 min.

Synthesis of9-(5-amino-2-methylphenyl)-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(from Peak 2)

A mixture of2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide(1.0 equiv: see Ex. 160) in 1:1 THF/MeOH (0.051 M) and NaOH (1 M aq, 10equiv) was heated to 75° C. and stirred for overnight. The mixture waspoured onto water and extracted three times with ethyl acetate. LCMS Thecombined organics were washed with brine, dried over magnesium sulfate,filtered, and concentrated to9-(5-amino-2-methylphenyl)-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-olwhich was used without further purification. LCMS (m/z) (M+H)=340.3,Rt=0.56 min.

Example 334:N-(3-(6-hydroxy-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Single Enantiomer from Peak 1 Intermediate)

9-(5-amino-2-methylphenyl)-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(from Peak 1 chiral intermediate) (1.0 equiv) and2-(trifluoromethyl)isonicotinic acid (1.1 equiv) were taken up in DMA(0.05 M) at 25° C. HOAT (1.3 equiv), iPr₂EtN (3 equiv), and EDC (1.3equiv) were added and the mixture was stirred overnight at 25° C. Themixture was poured onto water and extracted three times with ethylacetate. The combined organics were washed with water and brine, driedover magnesium sulfate, filtered, and concentrated. The residue waspurified by flash column chromatography over silica gel (heptane and0-100% EtOAc gradient) to provide.N-(3-(6-hydroxy-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 63% yield. LCMS (m/z) (M+H)=513.3, Rt=0.87 min. ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.12 (dd, J=5.0,1.2 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.2, 2.3 Hz, 1H), 7.63(d, J=2.2 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 4.40(s, 1H), 4.04 (dd, J=11.3, 3.0 Hz, 1H), 3.93 (dd, J=11.5, 3.4 Hz, 1H),3.81 (d, J=12.5 Hz, 1H), 3.63 (td, J=11.5, 2.8 Hz, 2H), 3.12 (dd,J=10.7, 3.2 Hz, 1H), 2.96 (td, J=12.2, 3.6 Hz, 1H), 2.27 (s, 3H), 1.14(s, 3H), 0.93 (s, 3H).

The following were prepared using the same methods as described forExample 334 using the appropriate starting materials:

335

N-(3-(6- hydroxy-5,5- dimethyl- 1,2,4,4a,5,6- hexahydro-[1.4]oxazino[4,3- a][1.5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.14-8.08 (m, 1H), 7.90 (d, J = 1.5Hz, 1H), 7.66 (dd, J = 8.2, 2.2 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.32(d, J = 8.3 Hz, 1H), 7.22 (d, J = 1.4 Hz, 1H), 4.40 (s, 1H), 4.04 (dd, J= 11.3, 3.0 Hz, 1H), 3.93 (dd, J = 11.5, 3.3 Hz, 1H), 3.81 (d, J = 12.3Hz, 1H), 3.63 (td, J = 11.5, 3.0 Hz, 2H), 3.11 (dd, J = 10.7, 3.1 Hz,1H), 2.96 (td, J = 12.2, 3.6 Hz, 1H), 2.27 (s, 3H), 1.14 (s, 3H), 0.93(s, 3H), LCMS (m/z) (M + H) = 513.3, Rt = 0.88 min 336

3-fluoro-N-(3- (6-hydroxy-5,5- dimethyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.65(d, J = 4.7 Hz, 1H), 7.95 (t, J = 4.8 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H),7.61 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.32 (d, J =8.2 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 4.40 (s, 1H), 4.04 (dd, J = 11.3,3.0 Hz, 1H), 3.93 (dd, J = 11.5, 3.4 Hz, 1H), 3.85- 3.76 (m, 1H), 3.62(td, J = 11.5, 2.9 Hz, 2H), 3.11 (dd, J = 10.7, 3.2 Hz, 1H), 2.96 (td, J= 12.2, 3.6 Hz, 1H), 2.26 (s, 3H), 1.14 (s, 3H), 0.93 (s, 3H). LCMS(m/z) (M + H) = 531.5, Rt = 0.90 min 337

3-fluoro-N-(3- (6-hydroxy-5,5- dimethyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.65(d, J = 4.7 Hz, 1H), 7.95 (t, J = 4.8 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H),7.61 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.32 (d, J =8.2 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 4.40 (s, 1H), 4.04 (dd, J = 11.3,3.1 Hz, 1H), 3.93 (dd, J = 11.5, 3.4 Hz, 1H), 3.85- 3.76 (m, 1H), 3.63(td, J = 11.5, 2.7 Hz, 2H), 3.47-3.32 (m, 2H), 3.10 (d, J = 3.2 Hz, 1H),2.96 (td, J = 12.2, 3.6 Hz, 1H), 2.26 (s, 3H), 1.14 (s, 3H), 0.93 (s,3H), LCMS (m/z) (M + H) = 531.3, Rt = 0.90 min

Synthesis of(10bR)-9-bromo-6-ethyl-4a-fluoro-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one

To a stirred solution of (4aR,10bS)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in THF (0.1 M) at −78° C. was added LDA (2 M inTHF/heptane/ethyl benzene, 1.3 equiv) and the mixture was stirred for 30min. N-fluorobenzenesulfonimide (1.3 equiv) was then added, and themixture was stirred for 30 min and the allowed to warm to RT over 1 h.The reaction was quenched with saturated aqueous NaHCO₃ and extractedtwice with EtOAc The combined organics were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified byflash column chromatography over silica gel (heptane and 0-50% EtOAcgradient) to provide(10bR)-9-bromo-6-ethyl-4a-fluoro-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-oneas a colorless oil in 82% yield. LCMS (m/z) (M+H)=329.0/331.0, Rt=1.06min.

Example 338:2-(1,1-difluoroethyl)-N-(3-((10bR)-6-ethyl-4a-fluoro-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide

A vial was charged with(10bR)-9-bromo-6-ethyl-4a-fluoro-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) and2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.05 equiv). THF (0.1 M) and K₃PO₄ (0.5 M aq, 2 equiv) were added, andthe flask was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos (0.05equiv) were added, and the reaction was heated at 45° C. for 1 h. Thereaction was diluted with DCM, dried over MgSO₄, filtered, andconcentrated. The residue was taken up in MeOH/DMSO with a bit of water,filtered, and purified by basic prep HPLC. Pure product fractions werelyophilized to2-(1,1-difluoroethyl)-N-(3-((10bR)-6-ethyl-4a-fluoro-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a fluffy white solid in 51% yield. The compound was a singlediastereomer, but the relative configuration of the fluoride was notdetermined. LCMS (m/z) (M+H)=525.3, Rt=1.22 min. ¹H NMR (400 MHz,DMSO-d6) δ 10.68 (s, 1H), 8.89 (d, J=5.0 Hz, 1H), 8.38 (d, J=2.2 Hz,1H), 8.19 (s, 1H), 8.04 (d, J=4.9 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.73(s, 2H), 7.37 (d, J=8.1 Hz, 1H), 4.42 (dd, J=10.9, 5.4 Hz, 1H), 4.19(ddq, J=26.9, 13.8, 6.9 Hz, 2H), 3.85-3.74 (m, 1H), 3.62 (td, J=10.9,5.6 Hz, 1H), 3.56-3.48 (m, 1H), 3.46 (dd, J=10.9, 5.5 Hz, 1H), 2.27 (s,3H), 2.12-1.96 (m, 4H), 1.69-1.55 (m, 1H), 1.21 (t, J=7.0 Hz, 3H).

The following were prepared using the same methods as described aboveusing the appropriate starting materials:

339

N-(3-((10bR)-6- ethyl-4a-fluoro-5- oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91(d, J = 5.0 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.12 (dd, J= 5.0, 1.2 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 6.2, 2.3 Hz,2H), 7.38-7.30 (m, 1H), 4.57 (dd, J = 11.0, 4.4 Hz, 1H), 4.36 (dq, J =13.8, 6.9 Hz, 1H), 4.26 (dd, J = 13.0, 7.0 Hz, 1H), 3.88 (dq, J = 11.2,4.0 Hz, 1H), 3.65-3.56 (m, 1H), 3.55-3.42 (m, 2H), 2.30 (s, 3H),2.12-2.04 (m, 1H), 1.69 (qd, J = 11.5, 4.3 Hz, 1H), 1.28 (t, J = 7.0 Hz,3H). LCMS (m/z) (M + H) = 529.3, Rt = 1.25 min 340

N-(5-((10bR)-6- ethyl-4a-fluoro-5- oxo- 2,4,4a,5,6,10b- hexahydro-1H-pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.87 (d, J= 2.4 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J = 7.9Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.05-7.97 (m, 2H), 7.82 (t, J = 7.8Hz, 1H), 4.41 (dd, J = 10.9, 5.8 Hz, 1H), 4.19 (ddq, J = 26.8, 13.7, 6.8Hz, 2H), 3.87-3.74 (m, 1H), 3.63 (ddd, J = 15.5, 11.1, 4.9 Hz, 1H),3.57- 3.50 (m, 1H), 3.49-3.42 (m, 1H), 2.48 (s, 3H), 2.07 (dd, J = 12.6,4.6 benzamide Hz, 1H), 1.72-1.57 (m, 1H), 1.21 (t, J = 7.0 Hz, 3H). LCMS(m/z) (M + H) = 529.3, Rt = 1.11 min

Examples 341:(N-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Single Enantiomer, “Peak 1”) and Example 342:N-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Single Enantiomer, “Peak 2”)

Step 1:

A stirred solution of ethyl4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate(1.0 equiv) in THF (0.1 M) was degassed with N₂; Pd(PPh₃)₄ (0.05 equiv)was then added, and the mixture was cooled to 0° C. Me₂Zn (2 M inheptane, 2.0 equiv) was subsequently added, and the reaction was allowedto warm to RT and stirred for 1 h. The reaction was quenched with brine,and the biphasic mixture was filtered through a pad of Celite. Thelayers of the filtrate were separated, and the organic layer was driedover sodium sulfate, filtered, and concentrated. The residue waspurified by flash column chromatography over silica gel (heptane and0-10% EtOAc gradient) to give ethyl4-methyl-5,6-dihydro-2H-pyran-3-carboxylate as a colorless oil in 83%yield. LCMS (m/z) Rt=0.82 min. ¹H NMR (400 MHz, Chloroform-d) δ 4.31 (h,J=2.1 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.77 (t, J=5.6 Hz, 2H), 2.31-2.23(m, 2H), 2.16 (dt, J=1.9, 1.1 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H)

Step 2:

A syringe was charged with a solution “Feed A”, prepared of ethyl4-methyl-5,6-dihydro-2H-pyran-3-carboxylate (1.0 equiv) and2-amino-5-bromopyridine (1.5 equiv) in THF (0.3 M). A second syringe“Feed B” was charged with LiHMDS (1 M in THF, 1.8 equiv). These syringeswere loaded onto separate syringe pumps and simultaneously injectedthrough a 500 ∞L PFA flow reactor submerged in a 65° C. oil bath at aflow rate of 65 μL/min for Feed A and 35 μL/min for Feed B. The elutingreaction mixture was directly quenched into saturated aqueous NH₄Cl. Thebiphasic mixture was extracted three times with ethyl acetate. Thecombined organics were sequentially washed with 1 M aq HCl, water,saturated aqueous NaHCO₃ and brine, dried over magnesium sulfate,filtered, and concentrated. The residue was adsorbed purified by flashcolumn chromatography over silica gel (heptane and 0-50% EtOAc) toprovideN-(5-bromopyridin-2-yl)-4-methyl-5,6-dihydro-2H-pyran-3-carboxamide as apale yellow solid in 45% yield. LCMS (m/z) (M+H)=296.9/238.9, Rt=0.87min. ¹H NMR (400 MHz, Chloroform-d) δ 8.36-8.33 (m, 1H), 8.30 (s, 1H),8.26-8.21 (m, 1H), 7.84 (dd, J=8.9, 2.4 Hz, 1H), 4.38 (h, J=2.0 Hz, 2H),3.84 (t, J=5.6 Hz, 2H), 2.20 (dq, J=4.8, 2.6 Hz, 2H), 1.97 (s, 3H).

Step 3:

To a stirred solution ofN-(5-bromopyridin-2-yl)-4-methyl-5,6-dihydro-2H-pyran-3-carboxamide (1.0equiv) in DMF (0.16 M) at 25° C. was added NaH (60% in mineral oil, 1.15equiv). The mixture was stirred for 10 min followed by the addition ofiodoethane (1.1 equiv) and the reaction was stirred for 30 min. Themixture was poured onto water and extracted three times with ethylacetate. The combined organics were washed with water and brine, driedover magnesium sulfate, filtered, and concentrated. The residue was andpurified by flash column chromatography over silica gel (heptane and0-70% EtOAc gradient) to giveN-(5-bromopyridin-2-yl)-N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamideas a colorless oil in 79% yield. LCMS (m/z) (M+H)=325.0/327.0, Rt=0.92min.

Step 4:

A vial was charged withN-(5-bromopyridin-2-yl)-N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamide(1.0 equiv) andN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.05 equiv). THF (0.1 M) and K₃PO₄ (0.5 M aq, 2.0 equiv) were added,and the vial was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos(0.05 equiv) were added, and the reaction was heated at 50° C. for 1 h.The reaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togiveN-(3-(6-(N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamido)pyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid in 100% yield. LCMS (m/z) (M+H)=525.2, Rt=1.15 min

Step 5:

A solution ofN-(3-(6-(N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamido)pyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv) in DMF (0.03 M) was charged to a quartz vial and irradiatedwith UVB lamps (Rayonet reactor, RPR3000 A bulbs) at RT overnight. Thereaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togive(rac)-N-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid in 86% yield. LCMS (m/z) (M+H)=525.2, Rt=1.26 min.

Step 6:

(rac)-N-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas subjected to chiral SFC (IB 21×250 mm column, 30% MeOH in CO₂eluent). The first eluting peak affordedN-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide“Peak 1” as a white solid in 36% yield. The second peak affordedN-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide“Peak 2” as a white solid in 31% yield. LCMS and NMR data for eachenantiomer were identical. LCMS (m/z) (M+H)=525.2, Rt=1.26 min. ¹H NMR(400 MHz, Methanol-d4) δ 8.81 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 8.18 (d,J=2.2 Hz, 1H), 8.05-8.01 (m, 1H), 7.57 (dd, J=6.5, 2.2 Hz, 2H), 7.53 (d,J=2.2 Hz, 1H), 7.29-7.20 (m, 1H), 4.23 (dq, J=13.9, 7.0 Hz, 1H),4.11-3.99 (m, 2H), 3.88 (dd, J=12.0, 4.0 Hz, 1H), 3.70 (td, J=12.3, 2.3Hz, 1H), 3.66-3.55 (m, 1H), 2.69 (dd, J=11.1, 4.5 Hz, 1H), 2.21 (s, 3H),1.98 (d, J=13.0 Hz, 1H), 1.87 (td, J=12.8, 5.0 Hz, 1H), 1.18-1.07 (m,6H).

Examples 343:2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide(Single Enantiomer, “Peak 1”) and 344:2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide(Single Enantiomer, “Peak 2”)

Step 1:

A vial was charged withN-(5-bromopyridin-2-yl)-N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamide(1.0 equiv) and2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.05 equiv). THF (0.1 M) and K₃PO₄ (0.5 M aq, 2.0 equiv) were added,and the vial was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos(0.05 equiv) were added, and the reaction was heated at 50° C. for 1 h.The reaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togive2-(1,1-difluoroethyl)-N-(3-(6-(N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamido)pyridin-3-yl)-4-methylphenyl)isonicotinamideas a white solid in 94% yield. LCMS (m/z) (M+H)=521.3, Rt=1.12 min

Step 2:

A solution of2-(1,1-difluoroethyl)-N-(3-(6-(N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamido)pyridin-3-yl)-4-methylphenyl)isonicotinamide(1.0 equiv) in DMF (0.015 M) was irradiated with UVA lamps (Rayonetreactor, RPR3500 A bulbs) at RT for 10 days. The reaction was pouredonto water and extracted twice with EtOAc The combined organics werewashed with water and brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (heptane and 0-100% EtOAc gradient) to give(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamideas a white solid in 38% yield. LCMS (m/z) (M+H)=525.2, Rt=1.21 min.

Step 3:

(rac)-2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamidewas subjected to chiral SFC (IA 21×250 mm column, 35% MeOH in CO₂eluent). The first eluting peak afforded2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide“Peak 1” as a white solid in 31% yield. The second peak afforded2-(1,1-difluoroethyl)-N-(3-((4a,10b-trans)6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide“Peak 2” as a white solid in 33% yield. LCMS and NMR data for eachenantiomer were identical. LCMS (m/z) (M+H)=525.2, Rt=1.21 min. ¹H NMR(400 MHz, Methanol-d4) δ 8.86-8.78 (m, 1H), 8.30 (d, J=2.2 Hz, 1H),8.23-8.15 (m, 1H), 7.99 (dd, J=5.1, 1.5 Hz, 1H), 7.72-7.63 (m, 3H),7.41-7.34 (m, 1H), 4.35 (dq, J=13.9, 7.0 Hz, 1H), 4.24-4.10 (m, 2H),4.00 (dd, J=12.0, 4.0 Hz, 1H), 3.82 (td, J=12.3, 2.3 Hz, 1H), 3.78-3.70(m, 1H), 2.82 (dd, J=11.1, 4.5 Hz, 1H), 2.33 (s, 3H), 2.16-1.93 (m, 5H),1.29-1.21 (m, 6H).

Examples 345 (“Peak 1”) and 346 (“Peak 3”) enantiomers ofN-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-1,4,4a,5,6,10b-hexahydro-2H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide

Step 1:

To a mixture ofN-(5-bromopyridin-2-yl)-N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamide(1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)nicotinamide(1.05 equiv.), XPhos Pd G2 (5 mol %) and XPhos (5 mol %) under anatmosphere of nitrogen was added degassed THF (0.14 M) and 0.5 M aq.K₃PO₄ (2 equiv.), and the reaction mixture was heated to 50° C. andstirred for 2 hours. The reaction was poured onto water and extractedtwice with EtOAc. The combined organics were washed with brine, driedover MgSO4, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography over silica (heptane with 0-90%ethyl acetate gradient) to affordN-(3-(6-(N-ethyl-4-methyl-5,6-dihydro-2H-pyran-3-carboxamido)pyridin-3-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamideas a white solid in 92% yield. LCMS (m/z) (M+H)=525.2, Rt=1.05 min. ¹HNMR (400 MHz, METHANOL-d4) δ ppm 9.34 (d, J=2.02 Hz, 1H), 9.07 (d,J=1.26 Hz, 1H), 8.66 (s, 1H), 8.47 (d, J=2.53 Hz, 1H), 7.87 (dd, J=8.21,2.40 Hz, 1H), 7.69 (dq, J=4.42, 2.23 Hz, 2H), 7.41 (d, J=8.34 Hz, 1H),7.32-7.39 (m, 1H), 4.21 (br d, J=2.02 Hz, 2H), 4.02 (q, J=7.07 Hz, 2H),3.62 (t, J=5.56 Hz, 2H), 2.26 (s, 3H), 1.89 (br s, 2H), 1.58 (s, 3H),1.22-1.26 (m, 3H).

Step 2:

A solution ofN-(3-(6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamidein DMF (0.05 M) was divided between 2 quartz vials and irradiated with aUVB lamp (Rayonet reactor, RPR3000 A bulbs) at room temperature for 17hours. The reaction was diluted with ethyl acetate, washed with water,brine, dried over MgSO4, filtered, and concentrated in vacuo. Theresidue was purified by chiral SFC (IX 30×250 mm 5 μM, 40% isopropanolin CO₂ eluent). The first eluted peak afforded a single enantiomer ofN-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide“Peak 1” as a white solid in 30% yield. The third eluted peak afforded asingle enantiomer ofN-(3-((4a,10b-trans)-6-ethyl-10b-methyl-5-oxo-2,4,4a,5,6,10b-hexahydro-1H-pyrano[3,4-c][1,8]naphthyridin-9-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide“Peak 3” as a white solid in 29% yield. The ¹H NMR and LCMS data matchedfor the two isolated enantiomers. LCMS (m/z) (M+H)=525.3, Rt=1.14. ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.65 (s, 1H), 9.38 (d, J=1.52 Hz, 1H),9.19 (d, J=1.26 Hz, 1H), 8.69 (s, 1H), 8.30 (d, J=2.27 Hz, 1H),7.67-7.77 (m, 2H), 7.63 (d, J=2.27 Hz, 1H), 7.36 (d, J=8.34 Hz, 1H),4.21 (dq, J=13.29, 6.85 Hz, 1H), 3.96-4.10 (m, 2H), 3.88 (br dd,J=11.75, 4.17 Hz, 1H), 3.54-3.79 (m, 2H), 2.79 (dd, J=11.12, 4.55 Hz,1H), 2.28 (s, 3H), 2.11 (br d, J=12.88 Hz, 1H), 1.82 (td, J=12.69, 4.67Hz, 1H), 1.10-1.19 (m, 6H).

The following were prepared using the same methods as described forExample 346 using the appropriate starting materials.

TABLE XX Ex. Structure Name Physical Data 347

N-(3-((4a,10b- trans)-6-ethyl-10b- methyl-5-oxo- 2,4,4a.5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-3-fluoro-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δppm 10.87 (s, 1 H), 8.76 (d, J = 4.80 Hz, 1 H), 8.29 (d, J = 2.02 Hz, 1H), 8.10 (t, J = 4.80 Hz, 1 H), 7.57- 7.70 (m, 3 H), 7.30-7.42 (m, 1 H),4.21 (dq, J = 13.29, 6.77 Hz, 1 H), 3.96-4.06 (m, 2 H), 3.87 (br dd, J =11.62, 4.55 Hz, 1 H), 3.56-3.74 (m, 2 H), 2.79 (dd, J = 10.99, 4.67 Hz,1 H), 2.27 (s, 3 H), 2.11 (br d, J = 13.14 Hz, 1 H), 1.81 (td, J =12.82, 4.93 Hz, 1 H), 1.10-1.19 (m, 6 H). LCMS (m/z) (M + H) = 542.8, Rt= 1.17 min. 348

N-(3-((4a,10b- trans)-6-ethyl-10b- methyl-5-oxo- 2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-4- methylphenyl)-3-fluoro-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δppm 10.87 (s, 1 H), 8.76 (d, J = 4.55 Hz, 1 H), 8.29 (d, J = 2.02 Hz, 1H), 8.10 (t, J = 4.93 Hz, 1H), 7.58- 7.67 (m, 3 H), 7.29-7.44 (m, 1 H),4.21 (dq, J = 13.17, 6.73 Hz, 1 H), 3.96-4.11 (m, 2 H), 3.87 (br dd, J =12.00, 4.17 Hz, 1 H), 3.55-3.74 (m, 2 H), 2.79 (dd, J = 10.86, 4.55 Hz,1 H), 2.27 (s, 3 H), 2.11 (br d, J = 12.88 Hz, 1 H), 1.81 (td, J =12.88, 5.05 Hz, 1 H), 1.10-1.19 (m, 6 H). LCMS (m/z) (M + H) = 543.2, Rt= 1.18 min. 349

N-(5-((4a,10b- trans)-6-ethyl-10b- methyl-5-oxo- 2,4,4a,5,6,10b-hexahydro-1H- pyrano[3,4- c][1,8]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-3- (trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d₄) δ 8.84(d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.31-8.29 (m, 1H), 8.24(d, 7.9 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H),7.77-7.73 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 4.39-4.29 (m, 1H),4.21-4.09 (m, 2H), 3.99 (dd, J = 11.7 Hz, 1H), 3.86-3.69 (m, 2H), 2.80(dd, J = 11.1, 4.5 Hz, 1H), 2.52 (s, 3H), 2.10 (d, J = 13.0 Hz, 1H),1.98 (td, J = 12.8, 5.0 Hz, 1H), 1.26-1.14 (m, 6H). LC-MS (m/z) (M + H)= 525.5; Rt = 2.15 min.

Examples 351:2-(1,1-difluoroethyl)-N-((5a,11b-trans)-3-(7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)isonicotinamide (Single Enantiomer, “Peak 1”) and 352:2-(1,1-difluoroethyl)-N-((5a,11b-trans)-3-(7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)isonicotinamide(Single Enantiomer, “Peak 2”)

Step 1:

A stirred solution of ethyl5-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydrooxepine-4-carboxylate(1.0 equiv) in THF (0.1 M) was degassed with N₂; Pd(PPh₃)₄ (0.05 equiv)was then added, and the mixture was cooled to 0° C. Me₂Zn (2 M inheptane, 2.0 equiv) was subsequently added, and the reaction was allowedto warm to RT and stirred for 3 h. The reaction was quenched with brine,stirred vigorously for 5 min, and then extracted twice with ethylacetate. The combined organics were washed with brine, dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash column chromatography over silica gel (heptane and 0-30% EtOAcgradient) to give ethyl 5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxylateas a colorless oil in quantitative yield. ¹H NMR (400 MHz, Chloroform-d)δ 4.21 (q, J=7.1 Hz, 2H), 3.69 (ddd, J=6.4, 3.0, 1.8 Hz, 4H), 2.75-2.63(m, 2H), 2.54-2.42 (m, 2H), 2.08 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).

Step 2:

A syringe was charged with a solution “Feed A”, prepared of ethyl5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxylate (1.0 equiv) and2-amino-5-bromopyridine (1.5 equiv) in THF (0.3 M). A second syringe“Feed B” was charged with LiHMDS (1 M in THF, 1.8 equiv). These syringeswere loaded onto separate syringe pumps and simultaneously injectedthrough a 500 μL PFA flow reactor submerged in a 65° C. oil bath at aflow rate of 65 μL/min for Feed A and 35 μL/min for Feed B. The elutingreaction mixture was directly quenched into saturated aqueous NH₄Cl. Thebiphasic mixture was extracted three times with ethyl acetate. Thecombined organics were sequentially washed with 1 M aq HCl, water,saturated aqueous NaHCO₃ and brine, dried over magnesium sulfate,filtered, and concentrated. The residue was adsorbed purified by flashcolumn chromatography over silica gel (heptane and 0-75% EtOAc) toprovideN-(5-bromopyridin-2-yl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamideas a white solid in 33% yield. LCMS (m/z) (M+H)=311.0/313.0, Rt=0.88 minmin. ¹H NMR (400 MHz, Chloroform-d) δ 8.36-8.32 (m, 1H), 8.24 (d, J=8.9Hz, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.85 (dd, J=8.9, 2.4 Hz, 1H), 3.79-3.75(m, 2H), 3.74-3.70 (m, 2H), 2.70-2.63 (m, 2H), 2.52-2.43 (m, 2H), 1.97(s, 3H).

Step 3:

To a stirred solution ofN-(5-bromopyridin-2-yl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(1.0 equiv) in DMF (0.1 M) at 25° C. was added NaH (60% in mineral oil,3.5 equiv). The mixture was stirred for 10 min followed by the additionof (2-bromoethoxy)-tert-butyldimethylsilane (3.0 equiv) and NaI (0.3equiv) and the reaction was stirred overnight at RT. The mixture waspoured onto water and extracted three times with ethyl acetate. Thecombined organics were washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated. The residue was and purified byflash column chromatography over silica gel (heptane and 0-70% EtOAcgradient) to giveN-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamideas a colorless oil in 46% yield. LCMS (m/z) (M+H)=325.0/327.0, Rt=0.92min.

Step 4:

A vial was charged withN-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(1.0 equiv) and2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.05 equiv). THF (0.1 M) and K₃PO₄ (0.5 M aq, 2.0 equiv) were added,and the vial was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos(0.05 equiv) were added, and the reaction was heated at 50° C. for 1 h.The reaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-80% EtOAc gradient) togiveN-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamideas a white foam in 72% yield. LCMS (m/z) (M+H)=665.3, Rt=1.50 min.

Step 5:

A solution ofN-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide(1.0 equiv) in DMF (0.03 M) was charged to a quartz vial and irradiatedwith UVB lamps (Rayonet reactor, RPR3000 A bulbs) at RT overnight. Thereaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The so-obtained residue was used as(rac)-N-(3-(7-((5a,11b-trans)-2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamidewithout further purification. LCMS (m/z) (M+H)=665.3, Rt=1.61 min.

Step 6:

To a stirred solution of(rac)-N-(3-(7-((5a,11b-trans)-2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide(1.0 equiv) in DCM (0.2 M) at 25° C. was added TfOH (1.5 equiv) and thereaction was stirred for 1 h. The mixture was partitioned between DCMand saturated aqueous NaHCO₃ and extracted three times with DCM. Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (heptane and 0-100% EtOAc gradient) to give(rac)-N-(3-(7-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)isonicotinamideas a white foam in 94% yield. LCMS (m/z) (M+H)=551.2, Rt=1.06 min.

Step 7:

(rac)-N-(3-(7-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)isonicotinamidewas subjected to chiral SFC (IA 21×250 mm column, 30% MeOH in CO₂eluent). The first eluting peak affordedN-(3-(7-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)isonicotinamide“Peak 1” as a white solid in 31% yield. The second peak affordedN-(3-(7-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)isonicotinamide“Peak 2” as a white solid in 35% yield. LCMS and NMR data for eachenantiomer were identical. LCMS (m/z) (M+H)=551.2, Rt=1.06 min. ¹H NMR(400 MHz, Methanol-d4) δ 8.80 (d, J=5.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H),8.18 (s, 1H), 7.96 (d, J=3.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.66 (dd,J=6.0, 2.3 Hz, 2H), 7.38-7.29 (m, 1H), 4.54 (dt, J=12.2, 6.0 Hz, 1H),4.23 (dt, J=13.2, 6.5 Hz, 1H), 3.99-3.93 (m, 1H), 3.90 (dt, J=8.3, 4.5Hz, 1H), 3.81 (ddt, J=12.6, 6.2, 3.5 Hz, 3H), 3.68 (td, J=12.0, 3.2 Hz,1H), 2.87 (dd, J=10.7, 1.7 Hz, 1H), 2.62-2.53 (m, 1H), 2.28 (d, J=6.0Hz, 5H), 2.03 (t, J=18.7 Hz, 4H), 1.18 (s, 3H).

Example 353:3-fluoro-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Single Enantiomer, “Peak 1”) and Example 354:3-fluoro-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Single Enantiomer, “Peak 2”)

Step 1:

A vial was charged withN-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(1.0 equiv) andN-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(1.05 equiv). THF (0.1 M) and K₃PO₄ (0.5 M aq, 2.0 equiv) were added,and the vial was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos(0.05 equiv) were added, and the reaction was heated at 50° C. for 1 h.The reaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient) togiveN-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-3-fluoro-2-(trifluoromethyl)isonicotinamideas a pale yellow foam in 80% yield. LCMS (m/z) (M+H)=687.3, Rt=1.42 min.

Step 2:

A solution ofN-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-3-fluoro-2-(trifluoromethyl)isonicotinamide(1.0 equiv) in DMF (0.03 M) was charged to a quartz vial and irradiatedwith UVB lamps (Rayonet reactor, RPR3000 A bulbs) at RT overnight. Thereaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The so-obtained residue was used as(rac)-N-(3-(7-((5a,10b-trans)-2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-3-fluoro-2-(trifluoromethyl)isonicotinamidewithout further purification. LCMS (m/z) (M+H)=687.2, Rt=1.42 min.

Step 3:

To a stirred solution of(rac)-N-(3-(7-((5a,10b-trans)-2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-3-fluoro-2-(trifluoromethyl)isonicotinamide(1.0 equiv) in DCM (0.1 M) at 25° C. was added TfOH (1.5 equiv) and thereaction was stirred for 1 h. The mixture was partitioned between DCMand saturated aqueous NaHCO₃ and extracted three times with DCM. Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatographyover silica gel (heptane and 0-100% EtOAc gradient) to give(rac)-3-fluoro-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a pale yellow foam in 73% yield. LCMS (m/z) (M+H)=573.2, Rt=1.04 min.

Step 4:

(rac)-3-fluoro-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidewas subjected to chiral SFC (LC-2 21×250 mm column, 45% MeOH in CO₂eluent). The first eluting peak afforded3-fluoro-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide“Peak 1” as a white solid in 36% yield. The second peak afforded3-fluoro-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide“Peak 2” as a white solid in 34% yield. LCMS and NMR data for eachenantiomer were identical. LCMS (m/z) (M+H)=573.2, Rt=1.04 min. ¹H NMR(400 MHz, Methanol-d4) δ 8.65 (d, J=4.7 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H),7.96 (t, J=4.8 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.61 (dd, J=5.6, 2.3 Hz,2H), 7.37-7.30 (m, 1H), 4.54 (dt, J=13.0, 6.0 Hz, 1H), 4.23 (dt, J=13.2,6.6 Hz, 1H), 3.96 (ddd, J=11.6, 4.6, 2.5 Hz, 1H), 3.90 (dt, J=8.3, 4.5Hz, 1H), 3.81 (ddt, J=12.6, 6.2, 3.6 Hz, 3H), 3.68 (td, J=12.0, 3.3 Hz,1H), 2.87 (dd, J=10.7, 1.9 Hz, 1H), 2.58 (dt, J=13.1, 2.3 Hz, 1H), 2.28(d, J=5.7 Hz, 5H), 2.10-1.94 (m, 1H), 1.18 (s, 3H).

Examples 355 and 356:N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(single enantiomer, “Peak 1”) (355) andN-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Single Enantiomer, “Peak 2”) (356)

Step 1:

N-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(1 equiv) andN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.1 equiv) were dissolved into degassed dioxane (0.089 M) along withdegassed potassium phosphate (0.5M aq, 2 equiv) in a vial with apressure relieve screw cap. To this was added XPhos Pd G2 (0.05 equiv)and XPhos (0.05 equiv) and then the reaction was heated closed to 80° C.with stirring. After 16 hr the reaction was diluted with EtOAc andtreated with granular anhydrous Na₂SO₄. After decantation volatiles wereremoved and the residue was purified by flash column chromatography oversilica gel (heptane with 0-80% ethyl acetate gradient) to yield a lightamber oilyN-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 84% yield. LCMS (m/z) (M+H)=669.4, R_(t)=1.87 min.

Step 2:

N-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1 equiv) was dissolved into anhydrous DMF in a quartz test tube cappedwith a rubber septa. The reaction was irradiated with UVB lamps (Rayonetreactor, RPR3000 A bulbs) at RT overnight. After 16 hr the reaction waspoured into H₂O and extracted three times with EtOAc. Organics werecombined, washed with brine and dried over anhydrous granular Na₂SO₄.After filtration and evaporation the residue(rac)-N-(3-((5a,11b-trans)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide was obtained in 95% yield. LCMS (m/z) (M+H)=669.5,R_(t)=1.99 min.

Step 3:

(rac)-N-(3-((5a,11b-trans)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1 equiv) was dissolved into MeOH (0.031M) with HCl in methanol (1.25M,5 equiv). After 30 minutes stirring at RT the reaction was pH adjustedto ˜8 with saturated aqueous NaHCO₃ and the volatiles removed. Theresidue was partitioned between DCM and H2O. Organics were separated,washed with brine, and dried over solid granular Na₂SO₄. Afterfiltration the volatiles were removed to yield(rac)-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamidein 83% yield. LCMS (m/z) (M+H)=555.1, R_(t)=1.03 min.

Step 4:

(rac)-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide was subjected to chiral SFC (Chiralpak AD-H 21×250 mmcolumn, 25% MeOH in CO₂ eluent). The first eluting peak affordedN-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide “Peak 1” as a white powder in 29.3% yield. The secondeluting peak affordedN-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide “Peak 2” as a white powder in 25.7% yield. LCMS and NMRdata for each enantiomer were identical. LCMS (m/z) (M+H)=555.2202,Rt=3.43 min. ¹H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J=5.0 Hz, 1H),8.25 (s, 1H), 8.19 (d, J=1.9 Hz, 1H), 8.07 (d, J=4.7 Hz, 1H), 7.70 (d,J=1.9 Hz, 1H), 7.60 (dd, J=5.8, 2.2 Hz, 2H), 7.28 (d, J=9.0 Hz, 1H),4.48 (dt, J=12.4, 5.9 Hz, 1H), 4.18 (dt, J=13.1, 6.5 Hz, 1H), 3.95-3.80(m, 2H), 3.75 (dtt, J=10.8, 7.6, 4.1 Hz, 3H), 3.62 (td, J=11.9, 3.2 Hz,1H), 2.82-2.79 (m, 1H), 2.58-2.48 (m, 1H), 2.27-2.10 (m, 5H), 1.98 (dtd,J=15.8, 11.9, 4.8 Hz, 1H), 1.14 (s, 3H).

Examples 357 and 358:N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide(single enantiomer, “Peak 1”) (357) andN-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide(Single Enantiomer, “Peak 2”) (358)

Step 1:

N-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(105 mg, 0.224 mmol) andN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)nicotinamide(1 equiv) were dissolved into pre-degassed dioxane (0.089 M) along withdegassed potassium phosphate (0.5M aq, 2 equiv) in a vial with apressure relieve screw cap. To this was added XPhos Pd G2 (0.05 equiv)and XPhos (0.05 equiv) and then the reaction was heated closed to 80° C.with stirring. After 16 hr the reaction was diluted with EtOAc andtreated with granular anhydrous Na₂SO₄. After decantation volatiles wereremoved the residue was purified by flash column chromatography oversilica gel (heptane with 0-80% ethyl acetate gradient). Fractionscontaining product were combined and evaporated to yield a light amberoilyN-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamidein 79% yield. LCMS (m/z) (M+H)=669.3, R_(t)=1.39 min.

Step 2:

N-(3-(6-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamido)pyridin-3-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide(1 equiv) was dissolved into anhydrous DMF in a quartz test tube cappedwith a rubber septa. The reaction was irradiated with UVB lamps (Rayonetreactor, RPR3000 A bulbs) at RT overnight. After 16 hr the reaction waspoured into H₂O and extracted three times with EtOAc. Organics werecombined, washed with brine and dried over anhydrous granular Na₂SO₄.After filtration and evaporation the residue(rac)-N-(3-((5a,11b-trans)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamidewas obtained in 92% yield. LCMS (m/z) (M+H)=669.1, R_(t)=1.49 min.

Step 3:

(rac)-N-(3-((5a,11b-trans)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide(1 equiv) was dissolved into MeOH (0.031M) with HCl in methanol (1.25M,5 equiv). After 30 minutes stirring at RT the reaction was pH adjustedto ˜8 with saturated aqueous NaHCO₃ and the volatiles were removed. Theresidue was partitioned between DCM and H₂O. The organics wereseparated, washed with brine and dried over solid granular Na₂SO₄. Afterfiltration the volatiles were removed to yield(rac)-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamidein 89% yield. LCMS (m/z) (M+H)=555.1, R_(t)=1.01 min.

Step 4:

(rac)-N-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide was subjected to chiral SFC (IC 30×250 mm column, 20% MeOHand 20% isopropanol in CO₂ eluent). The first eluting peak affordedN-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide “Peak 1” as a white powder in 16.5% yield. The secondeluting peak affordedN-(3-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide “Peak 2” as a white powder in 14.67% yield. LCMS and NMRdata for each enantiomer were identical. LCMS (m/z) (M+H)=555.2182,R_(t)=3.35 min. ¹H NMR (400 MHz, Methanol-d4) δ 9.25 (d, J=1.7 Hz, 1H),8.99-8.95 (m, 1H), 8.57 (s, 1H), 8.18-8.14 (m, 1H), 7.65 (dd, J=8.1, 2.1Hz, 1H), 7.56 (dq, J=4.3, 2.2 Hz, 2H), 7.27-7.22 (m, 1H), 4.44 (dt,J=12.1, 6.0 Hz, 1H), 4.14 (dt, J=13.2, 6.5 Hz, 1H), 3.90-3.77 (m, 2H),3.70 (dddd, J=17.3, 14.1, 6.8, 3.7 Hz, 3H), 3.63-3.53 (m, 1H), 2.77 (dd,J=10.7, 1.8 Hz, 1H), 2.49 (dd, J=15.7, 2.2 Hz, 1H), 2.23-2.14 (m, 5H),1.94 (dq, J=8.7, 3.8 Hz, 1H), 1.09 (s, 3H).

Examples 359 and 360:N-(5-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide(single enantiomer, “Peak 1”) (359) andN-(5-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide(Single enantiomer, “Peak 2”) (360)

Step 1:

N-(5-bromopyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-2,3,6,7-tetrahydrooxepine-4-carboxamide(105 mg, 0.224 mmol) andN-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(trifluoromethyl)benzamide(1 equiv) were dissolved into pre-degassed dioxane (0.089 M) along withdegassed potassium phosphate (0.5M aqueous, 2 equiv) in a vial with apressure relieve screw cap. To this was added XPhos Pd G2 (0.05 equiv)and XPhos (0.05 equiv) and then the reaction was heated closed to 80° C.with stirring. After 16 hr the reaction was diluted with EtOAc andtreated with granular anhydrous Na₂SO₄. After decantation volatiles wereremoved the residue was purified by flash column chromatography oversilica gel (heptane with 0-100% ethyl acetate gradient) to provide alight amber oilyN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-N-(2′-methyl-5′-(3-(trifluoromethyl)benzamido)-[3,3′-bipyridin]-6-yl)-2,3,6,7-tetrahydrooxepine-4-carboxamidein 66.7% yield. LCMS (m/z) (M+H)=669.2, R_(t)=1.28 min.

Step 2:

N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-methyl-N-(2′-methyl-5′-(3-(trifluoromethyl)benzamido)-[3,3′-bipyridin]-6-yl)-2,3,6,7-tetrahydrooxepine-4-carboxamide(1 equiv) was dissolved into anhydrous DMF in a quartz test tube cappedwith a rubber septa. The reaction was irradiated with UVB lamps (Rayonetreactor, RPR3000 A bulbs) at RT overnight. After 16 hr the reaction waspoured into H₂O and extracted three times with EtOAc. The organics werecombined, washed with brine and dried over anhydrous granular Na₂SO₄.After filtration and evaporation the residue(rac)-N-(5-((5a,11b-trans)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide was obtained in 89% yield. LCMS (m/z) (M+H)=669.2, R_(t)=1.37min.

Step 3:

N-(5-((rac)-N-(5-((5a,11b-trans)-7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (1 equiv) was dissolved into MeOH (0.031M) with HCl inmethanol (1.25M, 5 equiv). After 30 minutes stirring at RT the reactionwas pH adjusted to ˜8 with saturated aqueous NaHCO₃ and the volatilesremoved. The residue was partitioned between DCM and H₂O. The organicswere separated, washed with brine and dried over solid granular Na₂SO₄.After filtration the volatiles were removed to yield(rac)-N-(5-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamidein 82% yield. LCMS (m/z) (M+H)=555.07, R_(t)=0.86 min.

Step 4:

(rac)-N-(5-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamidewas subjected to chiral SFC (AS-H 21×250 mm column, 20% MeOH in CO₂eluent). The first eluting peak affordedN-(5-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide“Peak 1” as a white powder in 32.1% yield. The second eluting peakaffordedN-(5-((5a,11b-trans)-7-(2-hydroxyethyl)-11b-methyl-6-oxo-1,2,4,5,5a,6,7,11b-octahydrooxepino[4,5-c][1,8]naphthyridin-10-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide“Peak 2” as a white powder in 30.6% yield. LCMS and NMR data for eachenantiomer were identical. LCMS (m/z) (M+H)=555.2, R_(t)=0.87 min. ¹HNMR (400 MHz, Methanol-d4) δ 8.84 (d, J=2.5 Hz, 1H), 8.31 (d, J=2.2 Hz,2H), 8.24 (d, J=7.9 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.92 (d, J=7.8 Hz,1H), 7.83 (d, J=2.1 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 4.60-4.50 (m, 1H),4.24 (dt, J=13.1, 6.5 Hz, 1H), 4.02-3.87 (m, 2H), 3.87-3.76 (m, 3H),3.68 (td, J=12.0, 3.4 Hz, 1H), 2.92-2.85 (m, 1H), 2.59 (dd, J=15.7, 2.2Hz, 1H), 2.51 (s, 3H), 2.34-2.24 (m, 2H), 2.10-1.97 (m, 1H), 1.19 (s,3H).

Example 361:N-(3-((4a′R,10b′R)-6′-ethyl-1′,2′,4′,4a′,6′,10b′-hexahydrospiro[cyclopropane-1,5′-pyrano[3,4-c][1,8]naphthyridin]-9′-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:

To a stirred solution of(4aS,10bR)-9-bromo-6-ethyl-4,4a,6,10b-tetrahydro-1H-pyrano[3,4-c][1,8]naphthyridin-5(2H)-one(1.0 equiv) in THF (0.2 M) at 10° C. was addedmethyltitanium(IV)triisopropoxide (1 M in THF, 1.05 equiv) followed bydropwise addition of EtMgBr (1 M in THF, 2 equiv) and the mixture wasallowed to warm to RT and stirred overnight. The mixture was quenchedwith saturated aqueous NH₄Cl, stirred for 5 min, and then filteredthrough Celite, washing with EtOAc. The filtrate was partitioned betweenEtOAc and more saturated aqueous NH₄Cl and extracted three times withEtOAc. The combined organics were washed with brine, dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash column chromatography over silica gel (heptane and 0-60% EtOAcgradient) to give(4a′R,10b′R)-9′-bromo-6′-ethyl-1′,2′,4′,4a′,6′,10b′-hexahydrospiro[cyclopropane-1,5′-pyrano[3,4-c][1,8]naphthyridine]as a yellow oil in 32% yield. LCMS indicated about 70% purity; thematerial was used without further purification. LCMS (m/z)(M+H)=323.1/325.1, Rt=1.02 min.

Step 2:

A vial was charged with(4a′R,10b′R)-9′-bromo-6′-ethyl-1′,2′,4′,4a′,6′,10b′-hexahydrospiro[cyclopropane-1,5′-pyrano[3,4-c][1,8]naphthyridine](1.0 equiv) andN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.05 equiv). THF (0.05 M) and K₃PO₄ (0.5 M aq, 2.0 equiv) were added,and the vial was purged with N₂. XPhos Pd G2 (0.05 equiv) and XPhos(0.05 equiv) were added, and the reaction was heated at 50° C. for 1 h.The reaction was poured onto water and extracted twice with EtOAc Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography over silica gel (heptane and 0-100% EtOAc gradient).Product-containing fractions were concentrated and further purified bySFC (biphenyl 21×150 mm column, 10-20%% MeOH in CO₂ gradient eluent) togiveN-(3-((4a′R,10b′R)-6′-ethyl-1′,2′,4′,4a′,6′,10b′-hexahydrospiro[cyclopropane-1,5′-pyrano[3,4-c][1,8]naphthyridin]-9′-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid in 33% yield. LCMS (m/z) (M+H)=523.3, Rt=1.07 min. ¹HNMR (400 MHz, Methanol-d4) δ 8.90 (d, J=5.0 Hz, 1H), 8.30 (s, 1H),8.15-8.10 (m, 1H), 7.63 (dd, J=8.2, 2.3 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H),7.50-7.46 (m, 1H), 7.30 (d, J=8.3 Hz, 1H), 4.09-3.94 (m, 2H), 3.91 (dd,J=10.8, 4.2 Hz, 1H), 3.50 (td, J=12.3, 2.1 Hz, 1H), 3.27-3.21 (m, 1H),2.96-2.80 (m, 2H), 2.37-2.27 (m, 4H), 1.93 (td, J=11.2, 4.2 Hz, 1H),1.52 (qd, J=12.6, 4.6 Hz, 1H), 1.38-1.26 (m, 1H), 1.12 (t, J=7.0 Hz,3H), 1.01 (dt, J=10.6, 7.1 Hz, 1H), 0.58 (tq, J=11.4, 5.2 Hz, 2H).

Methodology Example(R)-6′-ethyl-1′,2′,4′,4a′,6′,10b′-hexahydrospiro[cyclopropane-1,5′-pyrano[3,4-c][1,8]naphthyridin]-9′-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

To a solution ofN-(3-(8-ethyl-7-oxo-7,8-dihydro-1,8-naphthyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1 equiv) in DMF (0.033 M) was added 4-methylenetetrahydro-2H-pyran (10equiv). The solution was then irradiated in RPR 200 Rayonet Reactorfitted with 3500A (UVA) lamps over a period of 72 hours. The reactionmixture was evaporated to a solid, dissolved in MeOH and purified bybasic reverse phase prep HPLC to giveN-(3-(4-ethyl-3-oxo-2a,2′,3,3′,4,5′,6′,8b-octahydro-2H-spiro[cyclobuta[c][1,8]naphthyridine-1,4′-pyran]-7-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamideas a white solid in 9% yield. LCMS (m/z) (M+H)=551.3, Rt=1.22 min. ¹HNMR (400 MHz, Methanol-d₄) δ 8.90 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.25(d, J=2.3 Hz, 1H), 8.12 (dd, J=5.0, 1.3 Hz, 1H), 7.70-7.62 (m, 2H),7.52-7.47 (m, 1H), 7.35 (d, J=8.2 Hz, 1H), 4.38-4.18 (m, 2H), 3.77 (dt,J=11.7, 3.6 Hz, 1H), 3.67-3.54 (m, 2H), 3.53-3.38 (m, 3H), 3.34-3.32 (m,1H, overlap with solvent), 2.70-2.59 (m, 1H), 2.31 (s, 3H), 1.93-1.69(m, 2H), 1.39 (td, J=12.4, 11.3, 3.7 Hz, 1H), 1.28 (dd, J=13.4, 2.1 Hz,1H), 1.22 (t, J=7.0 Hz, 3H).

The following were prepared using the same methods as described for thismethodology example, using the appropriate starting materials. Productswere purified by flash column chromatography over silica gel, HPLC,and/or SFC methods as appropriate:

362

(rac)-N-(3-(5- ethyl-6-oxo- 5,6,6a,6b,7,9,9a,9b- octahydrofuro[3′,4′:3,4]cyclobuta[1,2- c][1,8]naphthyridin- 2-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.90 (d, J = 5.0 Hz, 1H); 8.29 (m, 1H); 8.25 (d, J = 8.5 Hz, 1H); 8.12(m, 1H); 7.75-7.63 (m; 2H); 7.57 (d; J = 2.3 Hz, 1H); 7.34 (d, J = 9.1Hz, 1H); 4.30 (q, J = 7.0 Hz, 2H); 4.16 (dd, J = 14.2, 9.7 Hz, 2H);3.58-3.46 (m; 3H); 3.22-3.15 (m; 2H) 2.94-2.90 (m, 1H); 2.29 (s, 3H);1.26 (t, J = 7.0 Hz, 3H).; LCMS (m/z) (M + H) = 523.2, Rt = 2.55 min.

Example 363:(rac)-2-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Step 1:

(9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol(224 mg, 0.751 mmol) was charged into a vial and Et₃N (312 μl, 2.254mmol) and DCM (3.7 mL). The mixture was cooled to 0° C. and MsCl (64.4μl, 0.826 mmol) was added. The mixture agitated for 30 min and thenquenched by addition of water and Sat'd NH₄Cl. The product was extractedwith DCM. The organic layer was separated and dried (MgSO₄), filteredand concentrated in vacuo. The residue was dissolved in DMF (4.0 mL) andtreated with NaSMe (79 mg, 1.127 mmol). The mixture was agitated at roomtemperature for 30 min and then quenched by addition of Sat'd NaHCO₃ andwater. The product was extracted with EtOAc and the combined organicextract was washed with water twice and dried (MgSO₄), filtered andconcentrated in vacuo. The residue was dissolved in DMF (3.0 mL) andoxone (1385 mg, 2.254 mmol) was added in one portion. The mixture wasagitated at room temperature for 45 min after which Sodium bisulfite(1.00 gram) was added in portions and the dark green mixture wasagitated vigorously. Immediately, desired product is observed as themajor species. The mixture was diluted with EtOAc and filtered throughcelite. The filtrate was washed twice with water and dried (MgSO₄),filtered and concentrated in vacuo to afford 258 mg of9-bromo-5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline,which was taken to the next step as such without any furtherpurification. LCMS: (m/z) (M+H)=362.2, Rt=1.29 min.

Step 2:

9-bromo-5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline(60 mg, 0.167 mmol), PdCl₂(dppf).CH₂Cl₂ adduct (13.60 mg, 0.017 mmol),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(67.0 mg, 0.167 mmol) were combined in Dioxane (833 μl) and then 2MNa₂CO₃ (210 uL) was added. The mixture was agitated in MW at 130° C. for40 min and then the product extracted with EtOAc. The organic layer waspassed through a plug of anhydrous Na₂SO₄, and the filtrate concentratedin vacuo. The residue was purified by reverse-phase HPLC to afford thedesired productN-(4-methyl-3-(5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)phenyl)-2-(trifluoromethyl)isonicotinamideas free-base.

No. Structure Name Physical Data 363

(rac)-N-(4- methyl-3-(5- ((methylsulfonyl) methyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9- ¹H NMR (400 MHz, DMSO-d6) δppm 10.63 (s, 1 H) 8.99 (d, J = 4.89 Hz, 1 H) 8.36 (s, 1 H) 8.19 (dd, J= 5.01, 0.86 Hz, 1 H) 7.56-7.71 (m, 2 H) 7.29 (d, J = 8.31 Hz, 1 H) 7.06(d, J = 7.58 Hz, 1 H) 6.73-6.85 (m, 1 H) 6.67 (dd, J = 7.46, 1.34 Hz, 1H) yl)phenyl)-2- 3.95 (dd, J = 11.07, 2.87 Hz, 1 H) (trifluoromethyl)3.66-3.89 isonicotinamide (m, 2 H) 3.38-3.59 (m, 1 H) 3.27 (br d, J =1.47 Hz, 1 H) 2.84-3.13 (m, 5 H) 2.75 (dd, J = 15.47, 7.27 Hz, 1 H)2.29-2.41 (m, 1 H) 2.15-2.26 (m, 3 H); LCMS (m/z) (M + H—H₂O) = 560.4,Rt = 1.38 min. 364

(rac)-N-(6- methyl-5-(5- ((methylsulfonyl) methyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9- ¹H NMR (400 MHz, DMSO-d6) δppm 10.63 (s, 1 H) 8.66-9.00 (m, 1 H) 8.22-8.41 (m, 2 H) 7.93-8.10 (m, 2H) 7.81 (t, J = 7.83 Hz, 1 H) 6.99-7.16 (m, 1 H) 6.79-6.97 (m, 1 H)6.64-6.78 (m, 1 H) 3.72-4.02 (m, 3 H) 3.21-3.65 (m, 11 H) 2.68- 2.98 (m,3 H) 2.43 (s, 3 H) 2.36 yl)pyridin-3-yl)- (br d, J = 6.72 Hz, 1 H).;LCMS (m/z) 3- (M + H—H₂O) = 560.4, Rt = 1.28 min. (trifluoromethyl)benzamide 365

(rac)-2-(2- fluoropropan-2- yl)-N-(4-methyl- 3-(5- ((methylsulfonyl)methyl)- 1,2,4,4a,5,6- hexahydro- 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50(s, 1 H) 8.75 (d, J = 5.14 Hz, 1 H) 8.01 (s, 1 H) 7.81 (dd, J = 5.14,1.59 Hz, 1 H) 7.58-7.72 (m, 2 H), 7.27 (d, J = 8.31 Hz, 1 H) 7.03-7.12(m, 1 H) 6.73-6.88 (m, 1 H) 6.59-6.72 (m, 1 H) 3.68-4.04 (m, 3 H)3.40-3.62 (m, 2 H) 2.85- [1,4]oxazino[4,3- 3.14 (m, 5 H) 2.75 (dd, J =15.41, a]quinolin-9- 7.34 Hz, 1 H) 2.28-2.39 (m, 1 H) yl)phenyl)isonic2.17-2.26 (m, 3 H) 1.73 (s, 2 H) otinamide 1.70- 1.77 (m, 1 H) 1.68 (s,3 H); LCMS (m/z) (M + H) = 552.3. Rt = 1.36 min.

Example 366:(rac)-2-(1,1-difluoroethyl)-N-(3-(5-fluoro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide

Step 1:

(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol(85 mg, 0.751 mmol) was charged into a vial and Et₃N (119 μl, 0.855mmol) was added. To the mixture was then added MsCl (24.44 μl, 0.314mmol) and the mixture agitated for 30 min and then quenched by additionof water and Sat'd NH₄Cl. The product was extracted with DCM. Theorganic layer was separated and dried (MgSO₄), filtered and concentratedin vacuo. The residue was dissolved in DMF (4.0 mL) and treated withNaSMe (30.0 mg, 0.428 mmol). The mixture was agitated at roomtemperature. The mixture was agitated at room temperature for 30 minafter which the mixture was quenched with sat'd NaHCO₃ and water and theproduct extracted with EtOAc. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was dissolved in DMF(2.0 mL) and treated with oxone (526 mg, 0.855 mmol). The mixture wasagitated at room temperature for 45 min upon which LCMS indicatedcomplete formation of desired product. The mixture was diluted withEtOAc and filtered through celite. The filtrate was washed with watertwice and then dried (MgSO₄), filtered and concentrated in vacuo toafford 30.0 mg of the desired product9-chloro-5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine,which was taken to the next step as such without any furtherpurification. LCMS: (m/z) (M+H)=317.3, Rt=0.74 min.

Step 2:

9-chloro-5-((methylsulfonyl)methyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(15 mg, 0.047 mmol), X-Phos-Pd-G2 (3.72 mg, 4.73 μmol),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(19.05 mg, 0.047 mmol) and K₃PO₄ (30.2 mg, 0.142 mmol) were combined inDioxane (1 mL) and then water 150 uL was added. The mixture was agitatedin MW at 130° C. for 40 min and then the product extracted with EtOAc.The organic layer was passed through a plug of anhydrous Na₂SO₄, and thefiltrate concentrated in vacuo. The residue was purified byreverse-phase HPLC to afford the desired product as a free-base.

366

(rac)-2-(1,1- difluoroethyl)-N- (4-methyl-3-(5- ((methylsulfonyl)methyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin-¹H NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1 H) 8.88 (dd, J = 5.01, 0.61Hz, 1 H) 8.18 (d, J = 0.61 Hz, 1 H) 7.98-8.07 (m, 1 H) 7.83 (d, J = 1.22Hz, 1 H) 7.73 (dd, J = 8.25, 2.26 Hz, 1 H) 7.66 (d, J = 2.20 Hz, 1 H)7.32 (d, J = 8.44 Hz, 1 H) 7.21 (br s, 1 H) 4.05 (dd, J = 11.13. 2.69Hz, 1 9-yl)phenyl) H) 3.76-3.90 (m, 2 H) 3.41-3.69 isonicotinamide (m, 2H) 3.10-3.28 (m, 5 H) 3.06 (s, 3 H) 2.79- 2.96 (m, 2 H) 2.23 (s, 3 H)2.05 (t, J = 19.13 Hz, 3 H); LCMS (m/z) (M + H) = 557.4, Rt = 1.19 min.

Chiral Resolution of Intermediate X: the mixture of diastereomers ofthis tricyclic intermediate was separated by chiral SFC and was used tomake compounds in the tables below.

Ex. No. Structure Name Physical Data 367

3-(1,1- difluoroethyl)-N- (5-((4aS,5S)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- ¹H NMR(400 MHz, DMSO-d6 δ ppm 10.80 (s, 1 H) 8.90 (d, J = 5.01 Hz, 1 H) 8.83(d, J = 2.32 Hz, 1 H) 8.20 (s, 1 H) 7.95-8.08 (m, 2 H) 7.13 (d, J = 7.58Hz, 1 H) 6.84-6.93 (m, 1 H) 6.73-6.79 (m, 1 H) 5.30 (t, J = 5.81 Hz, 1H) 4.03 (dd, J = 11.13, 2.69 Hz, 1 H) 3.67-3.96 (m, 3 H) 3.37-3.66 (m. 4H) 2.78-3.25 (m, 4 methylpyridin-3- H) 2.44 (s, 3 H) 2.06 (t, J = 19.13Hz, yl)benzamide 3 H); LCMS (m/z) (M + H) = 513.2, Rt = 1.16 min. 368

3-(1,1- difluoroethyl)-N- (5-((4aR,5R)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H) 8.90 (d, J = 5.01 Hz, 1 H) 8.83(d, J = 2.32 Hz, 1 H) 8.20 (s, 1 H) 7.86-8.10 (m, 2 H) 7.13 (d, J = 7.58Hz, 1 H) 6.86 (s, 1 H) 6.75 (d, J = 7.58 Hz, 1 H) 5.75 (s, 1 H) 5.30 (t,J = 5.75 Hz, 1 H) 4.03 (dd, J = 11.13, 2.69 Hz, 1 H) 3.78-3.93 (m, 2 H)3.41-3.63 (m, 4 H) 2.99- methylpyridin-3- 3.30 (m, 2 H) 2.78-2.95 (m, 2H) yl)benzamide 2.44 (s, 3 H) 2.06 (t, J = 19.13 Hz, 3 H).; LCMS (m/z)(M + H) = 513.2, Rt = 1.16 min. 369

2-(1,1- difluoroethyl)-N- (3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.87 (d, J = 5.01 Hz, 1 H) 8.18(s, 1 H) 8.03 (br d, J = 4.65 Hz, 1 H) 7.56-7.73 (m, 2 H) 7.28 (d, J =8.31 Hz, 1 H) 7.09 (d, J = 7.58 Hz, 1 H) 6.78 (s. 1 H) 6.70 (d, J = 7.58Hz, 1 H) 5.29 (t, J = 5.75 Hz, 1 H) 4.03 (dd, J = 11.19, 2.75 Hz, 1 H)3.73-3.92 (m, 2 H) 3.43-3.64 (m, 4 methylphenyl) H) 3.01-3.29 (m, 2 H)2.73-2.92 isonicotinamide (m, 2 H) 2.23 (s, 3 H) 2.05 (t, J = 19.07 Hz,3 H).; LCMS (m/z) (M + H) = 512.2, 1.44 min. 370

2-(1,1- difluoroethyl)-N- (3-((4aR,5R)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.87 (d, J = 5.01 Hz, 1 H) 8.18(s, 1 H) 8.03 (br d, J = 4.65 Hz, 1 H) 7.56-7.73 (m, 2 H) 7.28 (d, J =8.31 Hz, 1 H) 7.09 (d, J = 7.58 Hz, 1 H) 6.78 (s, 1 H) 6.70 (d, J = 7.58Hz, 1 H) 5.29 (t, J = 5.75 Hz, 1 H) 4.03 (dd, J = 11.19, 2.75 Hz, 1 H)3.73-3.92 (m, 2 H) 3.43-3.64 (m, 4 methylphenyl) H) 3.01-3.29 (m, 2 H)2.73-2.92 isonicotinamide (m, 2 H) 2.23 (s, 3 H) 2.05 (t, J = 19.07 Hz,3 H).; LCMS (m/z) (M + H) = 512.2. 1.44 min. 371

2-(1,1- difluoroethyl)-N- (3-((4aS,5R)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.87 (br d, J = 4.89 Hz, 1 H)8.17 (s, 1 H) 8.02 (br d, J = 4.52 Hz, 1 H) 7.49-7.73 (m, 2 H) 7.28 (brd, J = 8.19 Hz, 1 H) 7.07 (br d, J = 7.58 Hz, 1 H) 6.80 (s, 1 H) 6.66(br d, J = 7.46 Hz, 1 H) 5.19 (br t, J = 5.44 Hz, 1 H) 3.78-4.04 (m, 3H) 3.39-3.76 (m, 6 H) 2.77-3.15 (m, 3 methylphenyl) H) 2.23 (s, 3 H)2.05 (br t, J = 19.13 isonicotinamide Hz, 3 H).; LCMS (m/z) (M + H) =512.2, 1.44 min. 372

2-(1,1- difluoroethyl)-N- (3-((4aR,5S)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H) 8.87 (br d, J = 4.89 Hz, 1 H)8.17 (s, 1 H) 8.02 (br d, J = 4.52 Hz, 1 H) 7.49-7.73 (m, 2 H) 7.28 (brd, J = 8.19 Hz, 1 H) 7.07 (br d, J = 7.58 Hz, 1 H) 6.80 (s, 1 H) 6.66(br d, J = 7.46 Hz, 1 H) 5.19 (br t, J = 5.44 Hz, 1 H) 3.78-4.04 (m, 3H) 3.39-3.76 (m, 6 H) 2.77-3.15 (m, 3 methylphenyl) H) 2.23 (s, 3 H)2.05 (br t, J = 19.13 isonicotinamide Hz, 3 H).; LCMS (m/z) (M + H) =512.2, 1.44 min. 373

N-(3-((4aR,5S)-5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.74-9.02 (m, 1 H) 8.18(s, 1 H) 8.03 (dd, J = 5.01, 1.34 Hz, 1 H) 7.71 (dd, J = 8.25, 2.26 Hz,1H) 7.64 (d, J = 2.20 Hz, 1 H) 7.29 (d, J = 8.44 Hz, 1 H) 7.08 (d, J =7.70 Hz, 1 H) 6.89 (d, J = 1.10 Hz, 1 H) 6.74 (dd, J = 7.64, 1.28 Hz, 1H) 4.19 (dd, J = 11.19, 3.12 Hz, 1 H) 3.79- isonicotinamide 4.03 (m, 2H) 3.58 (td, J = 11.74, 2.57 Hz, 1 H) 3.39 (t, J = 10.94 Hz, 1 H)3.03-3.15 (m, 3 H) 2.77 (td, J = 12.10, 3.67 Hz, 1 H) 2.24 (s, 3 H) 2.05(t, J = 19.13 Hz, 3 H) 1.43 (s, 3 H).; LCMS (m/z) (M + H) = 503.2, 1.47min. 374

N-(3-((4aS,5R)-5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.74-9.02 (m, 1 H) 8.18(s, 1 H) 8.03 (dd, J = 5.01, 1.34 Hz, 1 H) 7.71 (dd, J = 8.25, 2.26 Hz,1H) 7.64 (d, J = 2.20 Hz, 1 H) 7.29 (d, J = 8.44 Hz, 1 H) 7.08 (d, J =7.70 Hz, 1 H) 6.89 (d, J = 1.10 Hz, 1 H) 6.74 (dd, J = 7.64, 1.28 Hz, 1H) 4.19 (dd, J = 11.19, 3.12 Hz, 1 H) 3.79- isonicotinamide 4.03 (m, 2H) 3.58 (td, J = 11.74, 2.57 Hz, 1 H) 3.39 (t, J = 10.94 Hz, 1 H)3.03-3.15 (m, 3 H) 2.77 (td, J = 12.10, 3.67 Hz, 1 H) 2.24 (s, 3 H) 2.05(t, J = 19.13 Hz, 3 H) 1.43 (s, 3 H).; LCMS (m/z) (M + H) = 503.2, 1.47min. 375

N-(5-((4aR,5S)-5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-2-(1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H) 8.90 (dd,J = 5.01, 0.61 Hz, 1 H) 8.84 (d, J = 2.45 Hz, 1 H) 8.21 (d, J = 0.61 Hz,1 H) 7.96- 8.08 (m, 2 H) 7.12 (d, J = 7.70 Hz, 1 H) 6.97 (d, J = 1.22Hz, 1 H) 6.79 (dd, J = 7.58, 1.47 Hz, 1 H) 4.20 (dd, J = 11.19, 3.12 Hz,1 H) 3.84-4.04 (m, 2 H) 3.58 (td, J = 11.74, 2.69 Hz, isonicotinamide 1H) 3.36-3.46 (m, 1 H) 3.02-3.19 (m, 3 H) 2.79 (td, J = 12.10, 3.67 Hz, 1H) 2.44 (s, 3 H) 2.06 (t, J = 19.13 Hz, 3 H) 1.44 (s, 3 H).; LCMS (m/z)(M + H) = 504.1, 1.29 min. 376

N-(5-((4aS,5R)-5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-2-(1,1-difluoroethyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H) 8.90 (dd,J = 5.01, 0.61 Hz, 1 H) 8.84 (d, J = 2.45 Hz, 1 H) 8.21 (d, J = 0.61 Hz,1 H) 7.96- 8.08 (m, 2 H) 7.12 (d, J = 7.70 Hz, 1 H) 6.97 (d, J = 1.22Hz. 1 H) 6.79 (dd, J = 7.58, 1.47 Hz, 1 H) 4.20 (dd, J = 11.19, 3.12 Hz,1 H) 3.84-4.04 (m, 2 H) 3.58 (td, J = 11.74, 2.69 Hz, isonicotinamide 1H) 3.36-3.46 (m, 1 H) 3.02-3.19 (m, 3 H) 2.79 (td, J = 12.10, 3.67 Hz, 1H) 2.44 (s, 3 H) 2.06 (t, J = 19.13 Hz, 3 H) 1.44 (s, 3 H).; LCMS (m/z)(M + H) = 504.1, 1.29 min.

The following compounds were prepared using same procedure used forexamples 367-376, except that 3,5-dichloropicolinaldehyde was used inthe first step.

Ex. No. Structure Name Physical Data 377

N-(3-((4aR,5R)-5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.92(d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.2, 2.3 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 4.30-4.24(m, 1H), 4.04 (dd, J = 11.5, 3.7 Hz, 1H), 3.80 (dd, J = 12.2, 2.0 Hz,1H), 3.72 (td, J = 11.8, 2.9 Hz, 1H), 3.60 (t, J = 11.0 Hz, 1H),3.29-3.15 (m, 3H), 2.93 (td, J = 12.0, 3.8 Hz, 1H), 2.28 (s, 3H), 1.53(s, 3H). LCMS (m/z) (M + H) = 508.1, Rt = 1.15 min. 378

N-(3-((4aS,5S)-5- cyano-5-methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.92(d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.2, 2.3 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 4.27 (dd, J= 11.4. 3.0 Hz, 1H), 4.04 (dd, J = 11.5, 3.7 Hz, 1H), 3.84-3.77 (m, 1H),3.72 (td, J = 11.8, 2.9 Hz, 1H), 3.60 (t, J = 11.0 Hz, 1H), 3.28- 3.15(m, 3H), 2.93 (td, J = 12.0, .3.8 Hz, 1H), 2.28 (s, 3H), 1.53 (s, 3H).CMS (m/z) (M + H) = 508.1, Rt = 1.15 min.

The following compounds are derived from Peak 1 of the resolved chiralintermediate above:

379

N-(5-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-3(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.79 (s,1H), 8.29 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.07 (s, 1H), 7.91 (d, J =7.6 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.85(s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 4.07 (d, J = 11.2 Hz, 1H), 3.92 (d, J= 10.8 Hz, 1H), 3.77-3.54 (m, 5H), 3.28-3.08 (m, 2H), 3.07-2.87 (m, 2H),2.47 (s, 3H). LCMS (m/z) (M + H) = 516.2, Rt = 1.08 min. 380

3-fluoro-N-(3- ((4aS,5S)-5-fluoro- 5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4)oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.63(d, J = 4.7 Hz, 1H), 7.93 (t, J = 4.8 Hz, 1H), 7.56 (dd, J = 8.2, 2.2Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.12 (d, J= 7.5 Hz, 1H), 6.84-6.70 (m, 2H), 4.06 (dd, J = 11.4, 2.9 Hz, 1H), 3.91(dd, J = 11.2, 3.2 Hz, 1H), 3.74-3.52 (m, 5H), 3.25- 3.07 (m, 2H),3.04-2.86 (m, 2H), 2.24 (s, 3H), LCMS (m/z) (M + H) = 534.1. Rt = 1.51min. 381

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89 (d, J = 5.0 Hz,1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.61 (dd, J = 8.2,2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz. 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.12(d, J = 7.5 Hz, 1H), 6.80 (s, 1H), 6.76 (dd, J = 7.5, 1.4 Hz, 1H), 4.06(dd, J = 11.4, 3.2 Hz, 1H), 3.92 (dd, J = 11.2, 3.5 Hz, 1H) 3.74-3.53(m, 5H), 3.25-3.07 (m, 2H), 3.05-2.86 (m, 2H), 2.25 (s, 3H). LCMS (m/z)(M + H) = 516.2, Rt = 1.49 min. 382

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89 (d, J = 5.0 Hz,1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.61 (dd, J = 8.2,2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.12(d, J = 7.5 Hz, 1H), 6.80 (s, 1H), 6.76 (dd, J =7.5, 1.4 Hz, 1H), 4.06(dd, J = 11.4, 3.2 Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H), 3.74-3.55(m, 5H), 3.25-3.07 (m, 2H), 3.05-2.86 (m, 2H), 2.25 (s, 3H). LCMS (m/z)(M + H) = 516.2, Rt = 1.48 min. 383

N-(5-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-3(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J= 2.5 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 2.5Hz, 1H), 7.94-7.87 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.6Hz, 1H), 6.85 (d, J = 1.3 Hz, 1H), 6.81 (dd, J = 7.5, 1.5 Hz, 1H), 4.07(dd, J = 11.4, 3.2 Hz, 1H), 3.97-3.88 (m, 1H), 3.76-3.56 (m, 5H),3.28-3.09 (m, 2H), 3.07-2.89 (m, 2H), 2.47 (s, 3H). LCMS (m/z) (M + H) =516.1, Rt = 1.08 min. 384

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide ¹H NMR (400 MHz, Methanol-d4) δ 9.86 (d, J =2.0 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.2, 2.3 Hz, 1H),7.59 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.6 Hz,1H), 6.79 (s, 1H), 6.76 (dd, J = 7.5, 1.5 Hz, 1H), 4.06 (dd, J = 11.4,3.2 Hz, 1H), 3.92 (dd, J = 11.2, 3.5 Hz, 1H), 3.73-3.53 (m, 5H),3.24-3.08 (m, 2H), 3.05-2.86 (m, 2H), 2.25 (s, 3H). LCMS (m/z) (M + H) =517.1, Rt = 1.42 min. 385

3-fluoro-N-(3- ((4aS,5S)-5-fluoro- 5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.63(d, J = 4.7 Hz, 1H), 7.93 (t, J = 4.8 Hz, 1H), 7.56 (dd, J = 8.2, 2.3Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.12 (d, J= 7.5 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 6.75 (dd, J = 7.5, 1.5 Hz, 1H),4.06 (dd, J = 11.4, 3.2 Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H),3.73-3.54 (m, 5H), 3.24- 3.08 (m, 2H), 3.04-2.86 (m, 2H), 2.24 (s, 3H).LCMS (m/z) (M + H) = 534.1, Rt = 1.50 min. 386

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.68 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.75 (dd, J = 5.1, 1.7 Hz, 1H),7.63- 7.52 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H),6.80 (s, 1H), 6.77 (dd, J = 7.5, 1.3 Hz, 1H), 4.06 (dd, J = 11.4, 3.1Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H), 3.75-3.52 (m, 5H), 3.24-3.08(m, 2H), 3.05-2.86 (m, 2H), 2.25 (s, 3H), 1.75 (s, 3H), 1.69 (s, 3H).LCMS (m/z) (M + H) = 508.2, Rt = 1.45 min. 387

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-5- (trifluoromethyl)nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.33 (d, J = 1.7 Hz, 1H),9.06 (s, 1H), 8.65 (s, 1H), 7.65-7.50 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H),7.12 (d, J = 7.5 Hz, 1H), 6.85-6.71 (m, 2H), 4.06 (dd, J = 11.4, 3.2 Hz,1H), 3.92 (dd, J = 11.2, 3.5 Hz, 1H), 3.75-3.55 (m, 5H), 3.24-3.12 (m,2H), 3.09-2.87 (m, 2H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 516.1, Rt =1.45 min. 388

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (trifluoromethyl)pyrimidine-4- carboxamide ¹H NMR (400 MHz, Methanol-d4) δ 9.25 (d, J =5.0 Hz, 1H), 8.37 (d, J = 5.0 Hz, 1H), 7.72-7.62 (m, 2H), 7.13 (d, J =7.5 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 6.78 (dd, J = 7.5, 1.5 Hz, 1H),4.07 (dd, J = 11.4, 3.2 Hz, 1H), 3.92 (dd, J = 11.2, 3.5 Hz, 1H), 3.75-3.53 (m, 5H), 3.24-3.09 (m, 2H), 3.06-2.87 (m, 2H), 2.26 (s, 3H). LCMS(m/z) (M + H) = 517.9, Rt = 1.52 min. 389

N-(3-((4aS,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazido[4,3- a]quinolin-9-yl)-4- methylphenyl)-6- (trifluoromethyl)picolinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.44 (d, J = 7.6 Hz, 1H),8.28 (t, J = 8.0 Hz, 1H), 8.03 (dd, J = 7.8, 0.9 Hz, 1H), 7.67-7.56 (m,2H), 7.28 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.82 (d, J =1.2 Hz, 1H), 6.78 (dd, J = 7.5, 1.5 Hz, 1H), 4.06 (dd, J = 11.4, 3.2 Hz,1H), 3.92 (dd, J = 11.1, 3.5 Hz, 1H), 3.74-3.52 (m, 5H), 3.25- 3.08 (m,2H), 3.05-2.86 (m, 2H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 517.0, Rt =1.58 min. 390

2-amino-N-(3- ((4aS,5S)-5-fluoro- 5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ7.58-7.50 (m, 2H), 7.35 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H),7.15 (s, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.79 (s, 1H), 6.76 (dd, J = 7.5,1.4 Hz, 1H), 4.06 (dd, J = 11.4, 3.2 Hz, 1H), 3.92 (dd, J = 11.2, 3.5Hz, 1H), 3.74-3.53 (m, 5H), 3.24-3.08 (m, 2H), 3.05- 2.86 (m, 2H), 2.24(s, 3H). LCMS (m/z) (M + H) = 531.2. Rt = 1.42 min. 391

2-chloro-N-(3- ((4aS,5S)-5-fluoro- 5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.25(d, J = 1.1 Hz, 1H), 8.19 (s, 1H), 7.61 (dd, J = 8.2, 2.3 Hz, 1H), 7.57(d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H),6.79 (s, 1H), 6.76 (dd, J = 7.5, 1.5 Hz, 1H), 4.06 (dd, J = 11.4, 3.2Hz, 1H), 3.92 (dd, J = 11.2, 3.5 Hz, 1H), 3.74-3.53 (m, 5H), 3.24-3.08(m, 2H), 3.04- 2.87 (m, 2H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 550.1.Rt = 1.62 min. 392

3-(2-aminopropan- 2-yl)-N-(3- ((4aS,5S)-5-fluoro- 5- (hydroxymethyl)-1,2,4,4a.5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4-methylphenyl)-5- (trifluoromethyl) benzamide ¹H NMR (400 MHz,Methanol-d4) δ 8.33 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.59 (dd, J =8.2, 2.3 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H),7.12 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 6.77 (dd, J = 7.5, 1.4 Hz, 1H),4.06 (dd, J = 11.4, 3.2 Hz, 1H), 3.92 (dd, J = 11.1, 3.5 Hz, 1H), 3.73-3.53 (m, 5H), 3.24-3.08 (m, 2H), 3.04-2.85 (m, 2H), 2.25 (s, 3H), 1.57(s, 6H). LCMS (m/z) (M + H) = 572.2, Rt = 1.14 min. 393

N-(3-((4aS,5S)- 5-fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9- yl)-4- methylphenyl)- 5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.29-10.82(m, 1 H) 9.37 (d, J = 1.83 Hz, 1 H) 9.18 (d, J = 1.22 Hz, 1 H) 7.54-7.85 (m, 2 H) 7.28 (d, J = 8.31 Hz, 1 H) 7.10 (d, J = 7.58 Hz, 1 H) 6.79(s, 1 H) 6.70 (dd, J = 7.52. 1.41 Hz, 1 H) 5.29 (t, J = 5.81 Hz, 1 H)4.03 (dd, J = 11.13, 3.06 Hz, 1H) 3.73-3.91 (m, 2 H) 3.44-3.62 (m, 4 H)3.19-3.29 (m, 1 H) 3.01-3.17 (m, 1 H) 2.77- 2.93 (m, 2 H) 2.23 (s, 3H);.; LCMS (m/z) (M + H) = 516.2, 1.43 min.

The following compounds were derived from Peak 2 of the above resolvedintermediate.

394

N-(5-((4aS,5R)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J =2.5 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 2.5Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.17 (d, J= 7.6 Hz, 1H). 6.85 (d, J = 1.3 Hz, 1H), 6.81 (dd, 7.5, 1.5 Hz, 1H),4.07 (dd, J = 11.4, 3.2 Hz, 1H), 3.92 (dd, J = 10.7, 3.0 Hz, 1H),3.77-3.54 (m, 5H), 3.26-3.10 (m, 2H), 3.07-2.88 (m, 2H), 2.47 (s, 3H).LCMS (m/z) (M + H) = 516.1, Rt = 1.08 min. 395

3-fluoro-N-(3- ((4aS,5R)-5-fluoro- 5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.64(d, J = 4.7 Hz, 1H), 7.94 (t, J = 4.8 Hz, 1H), 7.56 (dd, J = 8.2, 2.3Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.12 (d, J= 7.5 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 6.76 (dd, J = 7.5, 1.5 Hz, 1H),4.06 (dd, J = 11.4, 3.2 Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H),3.73-3.53 (m, 5H), 3.24- 3.08 (m, 2H), 3.04-2.86 (m, 2H), 2.24 (s, 3H).LCMS (m/z) (M + H) = 534.1, Rt = 1.51 min. 396

N-(3-((4aS,5R)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89 (d, J = 5.0 Hz,1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.61 (dd, J = 8.2,2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.12(d, J = 7.5 Hz, 1H), 6.79 (s, 1H), 6.76 (dd, J = 7.5, 1.4 Hz, 1H), 4.06(dd, J = 11.4, 3.2 Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H), 3.73-3.53(m, 5H), 3.24-3.08 (m, 2H), 3.04-2.86 (m, 2H), 2.25 (s, 3H). LCMS (m/z)(M + H) = 516.2, Rt = 1.51 min. 397

N-(3-((4aS,5R)- 5-fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 5-(trifluoromethyl)nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.32-10.75 (m, 1 H) 9.37 (d, J= 1.71 Hz, 1 H) 9.18 (d, J = 1.22 Hz, 1 H) 8.68 (s, 1 H) 7.57-7.76 (m, 2H) 7.28 (d, J = 8.31 Hz, 1 H) 7.03-7.15 (m, 1 H) 6.76-6.85 (m, 1 H)6.58-6.73 (m, 1 H) 5.19 (br s, 1 H) 2.80-4.11 (m, 13 H) 2.23 (s, 3 H).;LCMS (m/z) (M + H) = 516.2, 1.43 min.

The following Compounds were derived from Peak 3 of the above resolvedintermediate.

398

N-(3-((4aR,5R)- 5-fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 5-(trifluoromethyl)nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1 H) 9.34-9.40(m, 1 H) 9.18 (s, 1 H) 8.68 (s, 1 H) 7.68 (dd, J = 8.25, 2.14 Hz, 1 H)7.63 (d, J = 2.08 Hz, 1 H) 7.28 (d, J = 8.44 Hz, 1 H) 7.10 (d, J = 7.58Hz, 1 H) 6.76- 6.99 (m, 1 H) 6.70 (dd, J = 7.52, 1.16 Hz, 1 H) 5.29 (t,J = 5.81 Hz, 1 H) 4.03 (dd, J = 11.13, 2.93 Hz, 1 H) 3.69-3.90 (m, 2 H)3.39-3.61 (m, 4 H) 3.17-3.29 (m, 1 H) 3.01-3.17 (m, 1 H) 2.80-2.97 (m, 2H) 2.23 (s, 3 H).; LCMS (m/z) (M + H) = 516.2, 1.43 min.

The following Compounds were derived from Peak 4 of the above resolvedintermediate.

399

N-(3-((4aR,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 1H NMR(400 MHz, DMSO- d6) ä ppm 10.62 (s, 1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.36(s, 1 H) 8.19 (dd, J = 4.95, 1.04 Hz, 1 H) 7.68 (d, J = 8.44 Hz, 1H)7.62 (s, 1 H) 7.29 (d, J = 8.31 Hz, 1 H) 7.07 (d, J = 7.70 Hz, 1 H)6.77- 6.83 (m, 1 H) 6.66 (dd, J = 7.52, 1.28 Hz, 1 H) 5.19 (t, J = 5.75Hz, 1H) 3.73-4.00 (m, 3 H) 3.37- 3.70 (m, 5 H) 2.82-3.13 (m, 3 H) 2.23(s, 3 H).; LCMS (m/z) (M + H) = 516.1, 1.48 min. 400

N-(3-((4aR,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 1H NMR(400 MHz, DMSO- d6) ä ppm 10.50 (s, 1 H) 8.75 (d, J = 5.01 Hz, 1 H) 8.02(s, 1 H) 7.81 (dd, J = 5.01, 1.59 Hz, 1 H) 7.58-7.73 (m, 2 H) 7.27 (d, J= 8.31 Hz, 1 H) 7.07 (d, J = 7.58 Hz, 1 H) 6.80 (s, 1 H) 6.66 (dd, J =7.52, 1.28 Hz, 1 H) 5.19 (t, J = 5.69 Hz, 1 H) 3.74-4.01 (m, 3 H)3.38-3.70 (m, 5 H) 2.83- 3.11 (m, 3 H) 2.22 (s, 3 H) 1.63- 1.80 (m, 6H).; LCMS (m/z) (M + H) = 508.2, 1.44 min. 401

2-(2-cyanopropan-2- yl)-N-(3-((4aR,5S)-5- fluoro-5- (hydroxymethyl)-1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 1H NMR (400MHz, DMSO- d6) ä ppm 10.49 (s, 1 H) 8.80 (dd, J = 5.07, 0.67 Hz, 1 H)8.00 (s, 1 H) 7.86 (dd, J = 5.01, 1.47 Hz, 1 H) 7.67 (dd, J = 8.25, 2.14Hz, 1 H) 7.60 (d, J = 2.20 Hz, 1 H) 7.28 (d, J = 8.44 Hz, 1 H) 7.07 (d,J = 7.70 Hz, 1 H) 6.80 (s, 1 H) 6.66 (dd, J = 7.52, 1.28 Hz, 1 H) 5.19(t, J = 5.69 Hz, 1 H) 3.75-3.98 (m, 3 H) 3.40- 3.72 (m, 5 H) 2.81-3.08(m, 3 H) 2.20-2.33 (m, 3 H) 1.75-1.93 (m, 7 H).; LCMS (m/z) (M + H) =515.1, 1.41 min. 403

N-(3-((4aR,5S)-5- fluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1 H)9.91 (d, J = 1.96 Hz, 1 H) 8.67 (d, J = 2.08 Hz, 1 H) 7.67 (d, J = 8.53Hz, 1 H) 7.62 (s, 1 H) 7.27-7.39 (m, 1 H) 7.03- 7.12 (m, 1 H) 6.80 (s, 1H) 6.66 (dd, J = 7.58, 1.34 Hz, 1 H) 6.23- 6.24 (m, 1 H) 5.19 (t, J =5.75 Hz, 1 H) 3.76-3.97 (m, 3 H) 3.39- 3.72 (m, 5 H) 2.83-3.10 (m, 3 H)2.24 (s, 3 H).; LCMS (m/z) (M + H) = 517.1, 1.42 min. 404

N-(3-((4aR,5S)-5- fluoro-5-(hydroxyl- methyl)-1,2,4,4a,5,6-hexahydro-[1,4] oxazino[4,3-a] quinolin-9-yl)-4- methylphenyl)-5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H) 9.37 (d, J = 1.59 Hz, 1 H) 9.18 (s, 1 H) 8.68 (s, 1 H) 7.62-7.71 (m,1 H) 7.61 (s, 1 H) 7.28 (d, J = 8.44 Hz, 1 H) 7.07 (d, J = 7.58 Hz, 1 H)6.80 (s, 1 H) 6.67 (dd, J = 7.64, 1.28 Hz, 1 H) 5.19 (br s, 1 H)3.78-3.99 (m, 3 H) 3.37-3.73 (m, 6 H) 2.82- 3.13 (m, 4 H) 2.23 (s, 3H).; LCMS (m/z) (M + H) = 516.2, 1.43 min.

Intermediate for Example 405:(rac)-(9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol

ethyl9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(350 mg, 1.065 mmol) was dissolved in THF (10 mL) and then cooled inice-bath. super hydride (1.0 M in THF) (3.19 mL, 3.19 mmol) was addeddropwise and the mixture agitated in ice-bath for 60 min and thenquenched by addition of water and then sat'd Na₂CO₃. The product wasextracted with EtOAc and the organic layer was washed with Sat'd NH₄Cland then dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified by flash chromatography (0-70% EtOAc/heptane) to afford thedesired product as a white solid in a 80:20 diastereomeric ratio. Thismaterial was submitted for chiral separation, which afforded appreciablequantities of only the enantiomeric pairs from major diastereomer. LCMS(m/z) (M+H)=287.2, 0.64 min.

405

N-(3-((4aS,5S)-5- (fluoromethyl)-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1 H) 8.99(d, J = 5.01 Hz, 1 H) 8.36 (s, 1 H) 8.19 (dd, J = 4.95, 1.16 Hz, 1 H)7.85 (d, J = 1.71 Hz, 1H) 7.72 (dd, J = 8.25, 2.26 Hz, 1 H) 7.65 (d, J =2.20 Hz, 1 H) 7.33 (d, J = 8.44 Hz, 1 H) 7.25 (d, J = 1.59 Hz, 1 H) 5.04(t, J = 5.14 Hz, 1 H) 4.30-4.65 (m, 2 H) 3.74-4.06 (m, 3 H) 3.41-3.54isonicotinamide (m, 4 H) 3.29 (br s, 1 H) 2.83-2.98 (m, 2 H) 2.68 (d, J= 17.24 Hz, 1 H) 2.24 (s, 3 H); LCMS (m/z) (M + H) = 531.2, 0.89 min.406

N-(5-((4aS,5S)-5- (fluoromethyl)-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1 H) 8.86(d, J = 2.44 Hz, 1 H) 8.24-8.39 (m, 2 H) 8.05 (d, J = 2.45 Hz, 1 H) 8.00(d, J = 7.83 Hz, 1H) 7.90 (d, J = 1.59 Hz, 1 H) 7.76-7.85 (m, 1 H) 7.33(d, J = 1.59 Hz, 1 H) 5.05 (t, J = 5.14 Hz, 1 H) 4.30-4.65 (m, 2 H)3.80-4.08 (m, 3 H) 3.42-3.57 (m, 4 H) 2.84-3.05 methyl)benzamide (m, 2H) 2.69 (d, J = 17.24 Hz, 1 H) 2.44 (s, 3 H).; LCMS (m/z) (M + H) =531.2, 0.83 min. 407

2-(1,1- difluoroethyl)-N- (3-((4aS,5S)-5- (fluoromethyl)-5-(hydroxymethyl)- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9-yl)-4- ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H) 8.88(d, J = 5.01 Hz, 1 H) 8.18 (s, 1 H) 8.03 (dd, J = 5.01, 1.34 Hz, 1 H)7.86 (d, J = 1.59 Hz, 1H) 7.73 (dd, J = 8.31, 2.20 Hz, 1 H) 7.66 (d, J =2.20 Hz, 1 H) 7.32 (d, J = 8.44 Hz, 1 H) 7.26 (d, J = 1.34 Hz, 1 H) 5.04(br t, J = 4.71 Hz, 1 H) 4.25-4.68 (m, 2 H) 3.77-4.10 (m, 3 H) 3.43-3.62methylphenyl) (m, 4 H) 2.86-3.03 (m, 2 H) 2.68 (d, isonicotinamide J =17.36 Hz, 1 H) 2.24 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H).; LCMS (m/z)(M + H) = 527.2, 0.83 min. 408

N-(3-((4aR,5R)-5- (fluoromethyl)-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H) 8.88(d, J = 5.01 Hz, 1 H) 8.18 (s, 1 H) 8.03 (dd, J = 5.01, 1.34 Hz, 1 H)7.86 (d, J = 1.59 Hz, 1H) 7.73 (dd, J = 8.31, 2.20 Hz, 1 H) 7.66 (d, J =2.20 Hz, 1 H) 7.32 (d, J = 8.44 Hz, 1 H) 7.26 (d, J = 1.34 Hz, 1 H) 5.04(br t, J = 4.71 Hz, 1 H) 4.25- 4.68 (m, 2 H) 3.77-4.10 (m, 3 H) 3.43-isonicotinamide 3.62 (m, 4 H) 2.86-3.03 (m, 2 H) 2.68 (d, J = 17.36 Hz,1 H) 2.24 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H); LCMS (m/z) (M + H) =531.2, 0.86 min. 409

N-(5-((4aR,5R)-5- (fluoromethyl)-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H) 8.88(d, J = 5.01 Hz, 1 H) 8.18 (s, 1 H) 8.03 (dd, J = 5.01, 1.34 Hz, 1H)7.86 (d, J = 1.59 Hz, 1H) 7.73 (dd, J = 8.31, 2.20 Hz, 1 H) 7.66 (d, J =2.20 Hz, 1 H) 7.32 (d, J = 8.44 Hz, 1 H) 7.26 (d, J = 1.34 Hz, 1 H) 5.04(br t, J = 4.71 Hz, 1 H) 4.25-4.68 (m, 2 H) 3.77-4.10 (m, 3 H) 3.43-3.62methyl)benzamide (m, 4 H) 2.86-3.03 (m, 2 H) 2.68 (d, J = 17.36 Hz, 1 H)2.24 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H).; LCMS (m/z) (M + H) = 31.2,0.81 min. 410

2-(1,1- difluoroethyl)-N- (3-((4aR,5R)-5- (fluoromethyl)-5-(hydroxymethyl)- 1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3-a]quinolin-9-yl)-4- ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1 H) 8.86(d, J = 2.44 Hz, 1 H) 8.24-8.39 (m, 2 H) 8.05 (d, J = 2.45 Hz, 1 H) 8.00(d, J = 7.83 Hz, 1H) 7.90 (d, J = 1.59 Hz, 1 H) 7.76-7.85 (m, 1 H) 7.33(d, J = 1.59 Hz, 1 H) 5.05 (t, J = 5.14 Hz, 1 H) 4.30-4.65 (m, 2 H)3.80- 4.08 (m, 3 H) 3.42-3.57 (m, 4 H) 2.84- 3.05 (m, 2 H) 2.69 (d, J =17.24 Hz, methylphenyl) 1 H) 2.44 (s, 3 H).; LCMS (m/z) isonicotinamide(M + H) = 527.2, 0.83 min. 411

(S)-2-(1,1- difluoroethyl)- N-(4-methyl-3- (8-oxo- 1,2,4,4a,5,6-hexahydro-8H- pyrido[2′,1′:2,3] pyrimido[6,1- c][1,4]oxazin-10-yl)phenyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H) 8.88 (d, J= 5.01 Hz, 1 H) 8.18 (s, 1 H) 8.03 (d, J = 4.89 Hz, 1 H) 7.61-7.77 (m, 2H) 7.28 (d, J = 8.31 Hz, 1 H) 5.63 (d, J = 1.47 Hz, 1 H) 5.55 (d, J =1.47 Hz, 1 H) 3.90-4.07 (m, 2 H) 3.74-3.89 (m, 2 H) 3.63 (br d, J =12.96 Hz, 1 H) 3.53 (td, J = 11.68, 2.57 Hz, 1 H) 3.35 (br dd, J = 6.85,3.18 Hz, 1 H) 3.23-3.30 (m, 1 H) 3.07 (td, isonicotinamide J = 12.32,3.48 Hz, 1 H) 2.27 (s, 3 H) 2.18-2.19 (m, 1 H) 1.91-2.12 (m, 4 H)1.51-1.72 (m, 1 H).; LCMS (m/z) (M + H) = 481.0, 0.94 min. 412

(S)-2-(2- fluoropropan-2- yl)-N-(4-methyl- 3-(8-oxo- 1,2,4,4a,5,6-hexahydro-8H- pyrido[2′,1′:2,3] pyrimido[6,1- c][1,4]oxazin-10-yl)phenyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1 H) 8.75 (d, J= 5.14 Hz, 1 H) 8.01 (s, 1 H) 7.81 (dd, J = 5.07, 1.65 Hz, 1 H)7.62-7.75 (m, 2 H) 7.27 (d, J = 8.44 Hz, 1 H) 5.63 (d, J = 1.59 Hz, 1 H)5.54 (d, J = 1.59 Hz, 1 H) 3.92-4.02 (m, 2 H) 3.75-3.91 (m, 2 H) 3.63(br d, J = 12.96 Hz, 1 H), 3.53 (td, J = 11.68, 2.57 Hz, 1 H) 3.33- 3.43(m, 1 H) 3.20-3.29 (m, 1 H) isonicotinamide 3.07 (td, J = 12.32, 3.36Hz, 1 H) 2.26 (s, 3 H) 1.95-2.11 (m, 1 H) 1.73 (s, 3 H) 1.57-1.70 (m, 4H).; LCMS (m/z) (M + H) = 477.1, 0.95 min. 413

(R)-2-(1,1- difluoroethyl)- N-(4-methyl-3- (8-oxo- 1,2,4,4a,5,6-hexahydro-8H- pyrido[2′,1′:2,3] pyrimido[6,1- c][1,4]oxazin-10-yl)phenyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (s, 1 H) 8.76-9.01(m, 1 H) 8.18 (s, 1 H) 8.02 (dd, J = 4.95, 1.41 Hz, 1 H) 7.59-7.80 (m, 2H) 7.28 (d, J = 8.31 Hz, 1 H) 5.63 (d, J = 1.59 Hz, 1 H) 5.54 (d, J =1.59 Hz, 1 H) 3.91-4.05 (m, 2 H) 3.76-3.90 (m, 2 H) 3.63 (br d, J =12.96 Hz, 1 H) 3.53 (td, J = 11.68, 2.69 Hz, 1 H) 3.33-3.45 (m, 1 H)3.17-3.29 (m, 1 H) 3.07 (td, J = 12.32, 3.48 Hz, 1 H) 2.27isonicotinamide (s, 3 H) 1.93-2.13 (m, 4 H) 1.43-1.68 (m, 1H).; LCMS(m/z) (M + H) = 481.0, 0.94 min. 414

(R)-2-(2- fluoropropan-2- yl)-N-(4-methyl- 3-(8-oxo- 1,2,4,4a,5,6-hexahydro-8H- pyrido[2′,1′:2,3] pyrimido[6,1- c][1,4]oxazin-10-yl)phenyl) ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.31-10.60 (m, 1 H) 8.75(d, J = 5.01 Hz, 1 H) 8.02 (s, 1 H) 7.82 (dd, J = 5.01, 1.59 Hz, 1 H)7.54-7.74 (m, 2 H) 7.27 (d, J = 8.31 Hz, 1 H) 5.63 (d, J = 1.59 Hz, 1 H)5.54 (d, J = 1.47 Hz, 1 H) 3.95 (t, J = 5.81 Hz, 2 H) 3.76-3.89 (m, 2 H)3.63 (br d, J = 12.96 Hz, 1 H) 3.53 (td, J = 11.68, 2.57 Hz, 1 H) 3.33-3.40 (m, 1 H) 3.21-3.29 (m, 1 H) 3.07 isonicotinamide (td, J = 12.35,3.42 Hz, 1 H) 2.26 (s, 3 H) 1.93-2.13 (m, 1H) 1.74 (s, 3 H) 1.68 (s, 3H) 1.56-1.66 (m, 1 H)..; LCMS (m/z) (M + H) = 477.1, 0.95 min. Ex. No.Structure Name (NVP #) Physical Data 415

(R)-3-fluoro-N- (4-methyl-3-(8- oxo-1,2,4,4a,5,6- hexahydro-8H-pyrido[2′,1′:2,3] pyrimido[6,1- c][1,4]oxazin-10- yl)phenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.64(d, J = 4.7 Hz, 1H), 7.94 (t, J = 4.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.31-7.27 (m, 1H), 5.87 (d, J = 1.6 Hz, 1H), 5.77 (d, J = 1.6 Hz, 1H),4.27-4.14 (m, 1H), 4.07-3.97 (m, 1H), 3.97- 3.90 (m, 1H), 3.85 (d, J =8.8 Hz, 1H), 3.73-3.58 (m, 2H), 3.45-3.34 (m, 2H), 3.26-3.16 (m, 1H),2.30 (s, 3H), 2.21-2.07 (m, 1H), 1.82-1.69 (m, 1H). LCMS (m/z) (M + H) =503.1, Rt = 1.31 min. 416

(S)-3-fluoro-N-(4- methyl-3-(8-oxo- 1,2,4,4a,5,6- hexahydro-8H-pyrido[2′,1′:2,3] pyrimido[6,1- c][1,4]oxazin-10- yl)phenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.64(d, J = 4.7 Hz, 1H), 7.94 (t, J = 4.8 Hz, 1H), 7.63-7.53 (m, 2H), 7.29(d, J = 7.8 Hz, 1H), 5.87 (d, J = 1.6 Hz, 1H), 5.77 (d, J = 1.6 Hz, 1H),4.26-4.13 (m, 1H), 4.08-3.98 (m, 1H), 3.98- 3.90 (m, 1H), 3.85 (d, J =8.9 Hz, 1H), 3.72-3.59 (m, 2H), 3.45-3.36 (m, 2H), 3.26-3.16 (m, 1H),2.30 (s, 3H), 2.21-2.09 (m, 1H), 1.81-1.70 (m, 1H). LCMS (m/z) (M + H) =503.1, Rt = 1.30 min.

Example 41711-(5-amino-2-methylphenyl)-1,2,5,5a,6,7-hexahydro-4H,9H-pyrido[2′,1′:2,3]pyrimido[1,6-d][1,4]oxazepin-9-one

Step 1:

Into a 250 mL RB flask were charged 1,4-oxazepan-5-one (5 g, 43.4 mmol)and DCM (43.4 ml). To the mixture at room temperature under nitrogen wasadded triethyloxonium tetrafluoroborate (9.08 g, 47.8 mmol). The mixturewas agitated at room temperature overnight and the next morning, thereaction mixture was quenched by addition of Sat'd NaHCO₃. The organiclayer was separated and dried (MgSO₄), filtered and concentrated invacuo (30° C., 250 mmHg) to afford the crude5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine (5.76 g, 40.2 mmol, 93%yield). The crude product 5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine fromabove and 2,2-dimethyl-1,3-dioxane-4,6-dione (5.80 g, 40.2 mmol) weresuspended in benzene (40.2 ml) and then Et₃N (1.115 ml, 8.05 mmol) wasadded. The mixture was refluxed overnight. The next morning, the mixturewas concentrated in vacuo and the orange-brown syrup residue wasazeotroped with toluene (2×20 mL) and the residue2,2-dimethyl-5-(1,4-oxazepan-5-ylidene)-1,3-dioxane-4,6-dione was takento the next step as such without any further purification. The crude2,2-dimethyl-5-(1,4-oxazepan-5-ylidene)-1,3-dioxane-4,6-dione from abovewas dissolved in MeOH (108 ml) and then NaOMe (5.26 g, 97 mmol) wasadded in one portion. The mixture was agitated at reflux for overnightand then the mixture was concentrated in vacuo and the residueneutralized with ammonium chloride (Sa'td) and then with 6N HCl. Theproduct was extracted with EtOAc and the organic layer was dried(MgSO₄), filtered and concentrated in vacuo and the residue (E)-methyl2-(1,4-oxazepan-5-ylidene)acetate taken to the next step as such withoutany further purification. LCMS (m/z) (M+H)=172.2, 0.57 min.

Step 2:

(E)-methyl 2-(1,4-oxazepan-5-ylidene)acetate (2.82 g, 16.47 mmol) wassuspended in Dioxane (43.9 ml) and Acetic Acid (10.98 ml) and then atroom temperature was added NaBH₄ (0.623 g, 16.47 mmol) portionwise. Themixture was then agitated at room temperature for 30 min and thenconcentrated in vacuo. The residue was basified with Na₂CO₃ (Sat'd) anddissolved in EtOAc and washed with water. The organic layer was dried(MgSO4), filtered and concentrated in vacuo to afford 1.31 gram ofmethyl 2-(1,4-oxazepan-5-yl)acetate taken to the next step as such. LCMS(m/z) (M+H)=174.0, 0.12 min.

Step 3:

methyl 2-(1,4-oxazepan-5-yl)acetate (600 mg, 3.46 mmol),4-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-2,6-difluoropyridine(909 mg, 3.05 mmol), DIEA (1815 μl, 10.39 mmol) were combined in NMP(3464 μl) and the mixture heated in MW at 200 for 60 min. After theelapsed time, the reaction mixture was diluted with EtOAc and washedwith water (thrice) and brine and dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(0-20% EtOAc/heptane) to afford 733 mg of the desired product methyl2-(4-(4-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-6-fluoropyridin-2-yl)-1,4-oxazepan-5-yl)acetateas a faint yellow solid. LCMS (m/z) (M+H)=452.2, 1.83 min.

Step 4:

methyl2-(4-(4-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-6-fluoropyridin-2-yl)-1,4-oxazepan-5-yl)acetate(733 mg, 1.623 mmol) was dissolved in THF (16.2 ml) and cooled to 0° C.To the mixture was then added LiAlH₄ (1.0 M in THF) (3.25 ml, 3.25 mmol)dropwise. After 30 min, the reaction mixture was quenched by addition ofwater (66 uL) and then 15% NaOH (132 uL) and then water (198 uL). Themixture was agitated vigorously for 5 min and then diluted with EtOAcand MgSO₄ was added. The entire mixture was filtered and the filtrateconcentrated in vacuo to afford crude product2-(4-(4-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-6-fluoropyridin-2-yl)-1,4-oxazepan-5-yl)ethanol.LCMS (m/z) (M+H)=424.2, 1.34 min. The crude product from above wasdissolved in DCM (Volume: 1.62E+04 μl) and then Et3N (1125 μl, 8.12mmol) was added. The mixture was cooled to 0° C. and then MsCl (139 μl,1.785 mmol) was added. The mixture was agitated at 0° C. for 10 min andthen concentrated in vacuo. The residue was dissolved in THF (35 mL) andheated to reflux for 48 h. Accordingly, after a total of 48 h of reflux,Sat'd NaHCO₃ (30 mL) was added and the mixture refluxed for another 2 hand then cooled to room temperature and extracted with EtOAc. Thecombined organic layer was dried (MgSO₄), filtered and concentrated invacuo. the residue was purified by flash chromatography (0-10% MeOH/DCM)to afford the desired product11-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-1,2,5,5a,6,7-hexahydropyrido[2′,1′:2,3]pyrimido[1,6-d][1,4]oxazepin-9(4H)-one.LCMS (m/z) (M+H)=404.2, 1.09 min.

Step 5:

11-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-1,2,5,5a,6,7-hexahydropyrido[2′,1′:2,3]pyrimido[1,6-d][1,4]oxazepin-9(4H)-one(34 mg, 0.084 mmol), hydroxylamine hydrochloride (70.3 mg, 1.011 mmol)were suspended in EtOH (1.8 mL) and Water (0.600 mL) and thentriethylamine (0.070 mL, 0.506 mmol) was added. The mixture was agitatedat 95° C. (bath temperature) overnight. The next afternoon (ca˜18 h) themixture was concentrated in vacuo and the residue was extracted twicewith EtOAc. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was taken to the next step withoutany further purification. LCMS(m/z) (M+H)=326.1, 0.53 min.

417

(S)-2-(2- fluoropropan-2- yl)-N-(4-methyl- 3-(9-oxo- 1,2,5,5a,6,7-hexahydro- 4H,9H- pyrido[2′,1′:2,3] pyrimido[1,6- d][1,4]oxazepin- ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.51 (s, 1 H) 8.75 (d, J = 5.01 Hz, 1 H)8.01 (s, 1 H) 7.81 (dd, J = 5.07, 1.65 Hz, 1 H) 7.69 (dd, J = 8.25, 2.26Hz, 1 H) 7.63 (d, J = 2.32 Hz, 1 H) 7.26 (d, J = 8.44 Hz, 1 H) 5.46 (d,J = 1.47 Hz, 1 H) 5.36 (d, J = 1.47 Hz, 1 H) 4.05 (dt, J = 14.40, 5.21Hz, 1 H) 3.59-3.92 (m, 7 H) 3.40-3.54 (m, 1 H) 2.59-2.64 (m, 111-yl)phenyl) H) 2.26 (s, 3 H) 2.07 (td, J = 9.63, isonicotinamide 4.46Hz, 1 H) 1.84-1.98 (m, 2 H) 1.73 (s, 3 H) 1.68 (s, 3 H).; LCMS (m/z)(M + H) = 491.2, 0.94 min. 418

(S)-2-(2- fluoropropan-2- yl)-N-(4-methyl- 3-(9-oxo- 1,2,5,5a,6,7-hexahydro- 4H,9H- pyrido[2′,1′:2,3] pyrimido[1,6- d][1,4]oxazepin- ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.31-10.60 (m, 1 H) 8.75 (d, J = 5.01 Hz,1 H) 8.02 (s, 1 H) 7.82 (dd, J = 5.01, 1.59 Hz, 1 H) 7.54-7.74 (m, 2 H)7.27 (d, J = 8.31 Hz, 1 H) 5.63 (d, J = 1.59 Hz, 1 H) 5.54 (d, J = 1.47Hz, 1 H) 3.95 (t, J = 5.81 Hz, 2 H) 3.76-3.89 (m, 2 H) 3.63 (br d, J =12.96 Hz, 1 H) 3.53 (td, J = 11.68, 2.57 Hz, 1 H) 3.33-3.40 (m, 1 H)11-yl)phenyl) 3.21-3.29 (m, 1 H) 3.07 (td, isonicotinamide J = 12.35,3.42 Hz, 1 H) 2.26 (s, 3 H) 1.93-2.13 (m, 1H) 1.74 (s, 3 H) 1.68 (s, 3H) 1.56-1.66 (m, 1 H)..; LCMS (m/z) (M + H) = 491.2, 0.94 min.

The following compounds were made in a similar fashion as Example 418except for using 4-bromo-2,6-difluorobenzaldehyde in the first step andusing chiral SFC of intermediate.

Compounds Derived from Peak 2

419

N-(3-((6aR,8R)-5- ethyl-8-hydroxy-6- oxo-5,6,6a,7,8,9-hexahydropyrido[2,3- e]pyrrolo[1,2- a]pyrazin-2-yl)-4- methylphenyl)-3-fluoro-2- (trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ10.64 (s, 1 H) 8.99 (d, J = 5.01 Hz, 1H) 8.36 (s, 1 H) 8.19 (d, J = 5.24Hz, 1 H) 7.70 (d, J = 7.89 Hz, 1 H) 7.63 (d, J = 2.20 Hz, 1 H) 7.30 (d,J = 8.44 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.72, 1.04 Hz, 1 H) 5.27(t, J = 5.75 Hz, 1 H) 3.96 (br d, J = 13.08 Hz, 1 H) 3.89 (d, J = 2.69Hz, 1 H) 3.87 (br d, J = 2.69 Hz, 1 H) 3.77 (dd, J = 11.37, 2.81 Hz, 1H) 3.55-3.71 (m, 3 H) 3.37- 3.52 (m, 2 H) 2.80-3.08 (m, 3 H), 2.15-2.34(m, 3 H).; LCMS (m/z) (M + H) = 534.0, 1.52 min. 420

N-(3-((4aS,5S)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.60(s, 1 H) 8.88 (d, J = 5.01 Hz, 1 H) 8.18 (s, 1 H) 8.02 (dd, J = 5.01,1.34 Hz, 1 H) 7.71 (dd, J = 8.25, 2.26 Hz, 1 H) 7.64 (d, J = 2.20 Hz, 1H) 7.29 (d, J = 8.44 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.72, 1.04 Hz,1 H) 5.27 (t, J = 5.75 Hz, 1 H) 3.96 (br d, J = 13.08 Hz, 1 H) 3.88 (dd,J = 10.94, 2.63 Hz, 1 H) 3.77 (dd, J = 11.37, 2.69 Hz, 1 H) 3.55-3.72(m, 3 H) 3.35-3.52 (m, 2 H) 2.79- 3.10 (m, 3 H) 2.24 (s, 3 H) 2.05 (t, J= 19.13 Hz, 3 H).; LCMS (m/z) (M + H) = 530.1, 1.48 min. 421

N-(5-((4aS,5S)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ 10.64 (s,1 H) 8.85 (d, J = 2.45 Hz, 1 H) 8.23-8.44 (m, 2 H) 7.94- 8.14 (m, 2 H)7.81 (t, J = 7.76 Hz, 1 H) 6.75 (s, 1 H) 6.60 (dd, J = 9.72, 1.16 Hz, 1H) 5.28 (t, J = 5.75 Hz, 1 H) 4.00 (br d, J = 12.96 Hz, 1 H) 3.88 (dd, J= 11.00, 2.69 Hz, 1 H) 3.77 (dd, J = 11.37, 2.69 Hz, 1 H) 3.55-3.70 (m,3 H) 3.37-3.52 (m, 2 H) 2.76- 3.14 (m, 3 H) 2.44 (s, 3 H);.; LCMS (m/z)(M + H) = 534.1, 1.13 min. 422

N-(3-((4aS,5S)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.52(s, 1 H) 8.65-9.01 (m, 1 H) 8.01 (s, 1 H) 7.81 (dd, J = 5.07, 1.65 Hz, 1H) 7.70 (dd, J = 8.19, 2.20 Hz, 1H) 7.63 (d, J = 2.20 Hz, 1 H) 7.28 (d,J = 8.44 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.72, 1.04 Hz, 1 H) 5.26(br s, 1 H) 3.96 (br d, J = 12.96 Hz, 1 H) 3.88 (dd, J = 11.00, 2.69 Hz,1 H) 3.76 (dd, J = 11.31, 2.75 Hz, 1 H) 3.55-3.70 (m, 3 H) 3.37-3.52 (m,2 H) 2.77- 3.09 (m, 3 H) 2.23 (s, 3 H) 1.73 (s, 3H) 1.68 (s, 3 H).; LCMS(m/z) (M + H) = 526.1, 1.49 min. 423

N-(3-((4aS,5S)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO-d6) δ10.82 (br s, 1 H) 9.91 (d, J = 1.96 Hz, 1 H) 8.67 (d, J = 1.96 Hz, 1 H)7.69 (dd, J = 8.19, 2.32 Hz, 1 H) 7.62 (d, J = 2.20 Hz, 1 H) 7.32 (d, J= 8.31 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.78, 1.10 Hz, 1 H) 5.27 (t,J = 5.75 Hz, 1 H) 3.96 (br d, J = 13.08 Hz, 1 H) 3.88 (dd, J = 11.00,2.69 Hz, 1 H) 3.77 (dd, J = 11.31, 2.75 Hz, 1H) 3.55-3.72 (m, 3 H)3.38-3.52 (m, 2 H) 2.78-3.11 (m, 3 H) 2.24 (s, 3 H).; LCMS (m/z) (M + H)= 535.0, 1.45 min.

Compounds Derived from Peak 4

424

N-(3-((4aR,5R)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.64 (s,1 H) 8.99 (d, J = 4.89 Hz, 1 H) 8.36 (s, 1 H) 8.19 (dd, J = 4.95, 1.16Hz, 1 H) 7.70 (d, J = 8.47 Hz, 1H) 7.63 (d, J = 2.32 Hz, 1 H) 7.30 (d, J= 8.44 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.78, 1.10 Hz, 1 H) 5.27 (t,J = 5.75 Hz, 1 H) 3.96 (br d, J = 13.08 Hz, 1 H) 3.88 (dd, J = 11.00,2.69 Hz, 1 H) 3.77 (dd, J = 11.43, 2.75 Hz, 1 H) 3.55- 3.72 (m, 3 H)3.37-3.52 (m, 2 H) 2.74-3.12 (m, 3 H) 2.24 (s, 3 H.; LCMS (m/z) (M + H)= 534.1, 1.52 min. 425

N-(3-((4aR,5R)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.60(s, 1 H) 8.88 (br d, J = 4.77 Hz, 1 H) 8.18 (s, 1 H) 8.03 (br d, J =4.77 Hz, 1 H) 7.71 (br d, J = 8.31 Hz, 1H) 7.61-7.67 (m, 1 H) 7.29 (brd, J = 8.19 Hz, 1 H) 6.68 (s, 1 H) 6.53 (br d, J = 9.66 Hz, 1 H) 5.27(t, J = 5.44 Hz, 1 H) 3.97 (br d, J = 13.08 Hz, 1 H) 3.88 (br d, J =10.64 Hz, 1 H) 3.77 (br d, J = 11.25 Hz, 1 H) 3.57-3.72 (m, 3 H)3.39-3.53 (m, 2 H) 2.77- 3.12 (m, 3 H) 2.24 (s, 3 H) 1.86-2.14 (m, 3H).; LCMS (m/z) (M + H) = 530.1, 1.48 min. 426

N-(5-((4aR,5R)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ 10.64 (s,1 H) 8.85 (d, J = 2.45 Hz, 1 H) 8.25-8.35 (m, 2 H) 7.96-8.05 (m, 2 H)7.81 (t, J = 7.82 Hz, 1 H) 6.75 (s, 1 H) 6.60 (dd, J = 9.72, 1.16 Hz, 1H) 5.28 (t, J = 5.75 Hz, 1 H) 4.00 (br d, J = 12.96 Hz, 1 H) 3.88 (dd, J= 10.94, 2.63 Hz, 1 H) 3.77 (dd, J = 11.43, 2.75 Hz, 1 H) 3.55- 3.73 (m,3 H) 3.37-3.52 (m, 2 H) 2.82-3.13 (m, 3 H) 2.44 (s, 3 H);.; LCMS (m/z)(M + H) = 534.1, 1.13 min. 427

N-(3-((4aR,5R)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.52(s, 1 H) 8.75 (d, J = 5.15 Hz, 1 H) 8.01 (s, 1 H) 7.81 (dd, J = 5.01,1.59 Hz, 1 H) 7.71 (dd, J = 8.25, 2.26 Hz, 1 H) 7.63 (d, J = 2.20 Hz, 1H) 7.28 (d, J = 8.56 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.78, 1.10 Hz,1 H) 5.23-5.30 (m, 1 H) 3.96 (br d, J = 13.08 Hz, 1 H) 3.88 (dd, J =10.94, 2.63 Hz, 1 H) 3.55-3.79 (m, 4 H) 3.45-3.51 (m, 1 H) 3.38-3.52 (m,1 H) 3.26-3.45 (m, 5 H) 2.81-3.07 (m, 3 H) 2.21-2.34 (m, 3 H) 1.73 (s, 3H) 1.68 (s, 3 H).; LCMS (m/z) (M + H) = 526.1, 1.49 min. 428

N-(3-((4aR,5R)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO-d6) δ10.82 (br s, 1 H) 9.91 (d, J = 1.96 Hz, 1 H) 8.67 (d, J = 2.08 Hz, 1 H)7.69 (dd, J = 8.19, 2.32 Hz, 1 H) 7.62 (d, J = 2.20 Hz, 1 H) 7.32 (d, J= 8.44 Hz, 1 H) 6.67 (s, 1 H) 6.52 (dd, J = 9.78, 1.10 Hz, 1 H) 5.27 (t,J = 5.75 Hz, 1 H) 3.96 (br d, J = 12.84 Hz, 1 H) 3.88 (dd, J = 11.00,2.69 Hz, 1 H) 3.77 (dd, J = 11.31, 2.75 Hz, 1 H) 3.54- 3.72 (m, 3 H)3.37-3.53 (m, 2 H) 2.79-3.11 (m, 3 H) 2.24 (s, 3 H).; LCMS (m/z) (M + H)= 535.0, 1.45 min.

Compounds Derived from Peak 1

429

N-(3-((4aS,5R)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.65 (s,1 H) 8.99 (d, J = 5.01 Hz, 1 H) 8.36 (s, 1 H) 8.19 (dd, J = 4.95, 1.16Hz, 1 H) 7.70 (d, J = 7.88 Hz, 1H) 7.64 (s, 1 H) 7.30 (d, J = 8.44 Hz, 1H) 6.66 (s, 1 H) 6.56 (dd, J = 9.72, 1.04 Hz, 1 H) 5.35 (t, J = 5.87 Hz,1 H) 4.07 (dd, J = 11.13, 3.06 Hz, 1H) 3.81-3.92 (m, 2 H) 3.44-3.71 (m,4 H) 3.38-3.38 (m, 1 H) 3.26-3.32 (m, 1 H) 2.80-3.07 (m, 3 H) 2.19- 2.34(m, 3 H);.; LCMS (m/z) (M + H) = 534.1, 1.52 min.. 430

N-(3-((4aS,5R)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO- d6) δ 10.60(s, 1 H) 8.88 (d, J = 5.20 Hz, 1 H) 8.18 (s, 1 H) 8.03 (dd, J = 5.01,1.47 Hz, 1 H) 7.71 (d, J = 7.92 Hz, 1H) 7.65 (s, 1 H) 7.29 (d, J = 8.44Hz, 1 H) 6.66 (s, 1 H) 6.56 (dd, J = 9.66, 1.10 Hz, 1 H) 5.35 (t, J =5.81 Hz, 1 H) 4.07 (dd, J = 11.07, 3.12 Hz, 1 H) 3.79-3.92 (m, 2 H)3.44- 3.76 (m, 4 H) 3.35 (dd, J = 10.70, 3.12 Hz, 1 H) 2.79-3.08 (m, 3H) 2.24 (s, 3 H) 2.05 (t, J = 19.13 Hz, 3 H).; LCMS (m/z) (M + H) =530.1, 1.48 min. 431

N-(5-((4aS,5R)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, DMSO- d6) δ 10.64 (s, 1H) 8.85 (d, J = 2.45 Hz, 1 H) 8.25-8.35 (m, 2 H) 8.03 (s, 1 H) 7.99 (d,J = 7.57 Hz, 1 H) 7.81 (t, J = 7.82 Hz, 1 H) 6.73 (s, 1 H) 6.64 (dd, J =9.60, 1.16 Hz, 1 H) 5.36 (t, J = 5.87 Hz, 1 H) 4.07 (dd, J = 11.13, 3.06Hz, 1 H) 3.81- 3.94 (m, 2 H) 3.45-3.77 (m, 4 H) 3.33-3.41 (m, 1 H) 2.82-3.06 (m, 3 H) 2.44 (s, 3 H).; LCMS (m/z) (M + H) = 534.1, 1.134 min. 432

N-(3-((4aS,5R)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.52 (s,1 H) 8.75 (d, J = 5.01 Hz, 1 H) 8.02 (s, 1 H) 7.82 (dd, J = 5.07, 1.65Hz, 1 H) 7.70 (d, J = 8.49 Hz, 1H) 7.64 (d, J = 2.20 Hz, 1 H) 7.28 (d, J= 8.44 Hz, 1 H) 6.66 (s, 1 H) 6.56 (dd, J = 9.78, 1.10 Hz, 1 H) 5.35 (s,1 H) 4.06 (dd, J = 11.19, 3.12 Hz, 1 H) 3.80-3.91 (m, 2 H) 3.44- 3.70(m, 4 H) 3.34 (dd, J = 10.64, 3.06 Hz, 1 H) 2.81-3.08 (m, 3 H) 2.21-2.34(m, 3 H) 1.72-1.78 (m, 3 H) 1.68 (s, 3H).; LCMS (m/z) (M + H) = 526.1,1.49 min. 433

N-(3-((4aS,5R)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO- d6) δ10.82 (br s, 1 H) 9.91 (d, J = 1.96 Hz, 1 H) 8.67 (d, J = 1.96 Hz, 1 H)7.69 (dd, J = 8.25, 2.26 Hz, 1 H) 7.63 (d, J = 2.32 Hz, 1 H) 7.32 (d, J= 8.44 Hz, 1 H) 6.66 (s, 1 H) 6.56 (dd, J = 9.72, 1.04 Hz, 1 H) 5.35 (t,J = 5.81 Hz, 1 H) 4.07 (dd, J = 11.13, 3.18 Hz, 1 H) 3.77-3.90 (m, 2 H)3.42-3.69 (m, 4 H) 3.32- 3.39 (m, 1 H) 2.80-3.06 (m, 3 H) 2.25 (s, 3H).; LCMS (m/z) (M + H) = 535.0, 1.45 min. 434

N-(3-((4aS,5R)-5,7- difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H) 9.37 (d, J = 1.83 Hz, 1 H) 9.18 (d, J = 1.22 Hz, 1 H) 8.55-8.75 (m, 1H) 7.70 (d, J = 8.48 Hz, 1H) 7.62-7.68 (m, 1 H) 7.30 (d, J = 8.44 Hz, 1H) 6.66 (s, 1 H) 6.56 (dd, J = 9.78, 1.10 Hz, 1 H) 5.35 (t, J = 5.81 Hz,1 H) 4.07 (dd, J = 11.13, 3.06 Hz, 1H) 3.78- 3.93 (m, 2 H) 3.44-3.68 (m,4 H) 3.32-3.38 (m, 1 H) 2.79-3.11 (m, 3 H) 2.24 (s, 3 H).; LCMS (m/z)(M + H) = 534.1, 1.41 min.

Compounds Derived from Peak 3

436

N-(3-((4aR,5S)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2- (1,1-difluoroethyl) isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H) 8.88 (d, J = 5.11 Hz, 1 H) 8.18 (s, 1 H) 8.03 (dd, J = 5.01, 1.47 Hz,1 H) 7.71 (d, J = 7.92 Hz, 1H) 7.65 (s, 1 H) 7.29 (d, J = 8.44 Hz, 1 H)6.66 (s, 1 H) 6.56 (dd, J = 9.72, 1.04 Hz, 1 H) 5.35 (t, J = 5.81 Hz, 1H) 4.07 (dd, J = 11.07, 3.12 Hz, 1 H) 3.81-3.93 (m, 2 H) 3.42-3.72 (m, 4H) 3.35 (dd, J = 10.70, 3.12 Hz, 1 H) 2.80-3.07 (m, 3 H) 2.24 (s, 3 H)2.05 (t, J = 19.13 Hz, 3 H).; LCMS (m/z) (M + H) = 530.1, 1.49 min. 437

N-(5-((4aR,5S)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, DMSO-d6) δ10.51-10.72 (m, 1 H) 8.85 (d, J = 2.45 Hz, 1 H) 8.21-8.39 (m, 2 H)7.94-8.11 (m, 2 H) 7.81 (t, J = 7.83 Hz, 1 H) 6.74 (s, 1 H) 6.64 (dd, J= 9.60, 1.16 Hz, 1 H) 5.36 (t, J = 5.87 Hz, 1 H) 4.07 (dd, J = 11.13,3.06 Hz, 1 H) 3.81-3.94 (m, 2 H) 3.42-3.78 (m, 4H) 3.37 (br dd, J =10.64, 2.93 Hz, 1 H) 2.81-3.10 (m, 3 H) 2.44 (s, 3 H).; LCMS (m/z) (M +H) = 534.1. 1.14 min. 438

N-(3-((4aR,5S)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.52(s, 1 H) 8.67-8.83 (m, 1 H) 8.02 (s, 1 H) 7.82 (dd, J = 5.07, 1.65 Hz, 1H) 7.70 (dd, J = 8.19, 2.20 Hz, 1H) 7.64 (d, J = 2.20 Hz, 1 H) 7.28 (d,J = 8.56 Hz, 1 H) 6.66 (s, 1 H) 6.56 (dd, J = 9.78, 1.10 Hz, 1 H) 5.35(br s, 1 H) 4.06 (dd, J = 11.13, 3.18 Hz, 1 H) 3.76-3.92 (m, 2 H)3.44-3.67 (m, 4 H) 3.32-3.38 (m, 1 H) 2.82- 3.07 (m, 3 H) 2.23 (s, 3 H)1.60-1.77 (m, 6 H).; LCMS (m/z) (M + H) = 526.1, 1.49 min. 439

N-(3-((4aR,5S)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz, DMSO-d6) δ10.82 (br s, 1 H) 9.91 (d, J = 1.83 Hz, 1 H) 8.67 (d, J = 2.08 Hz, 1 H)7.58- 7.78 (m, 2 H) 7.32 (d, J = 8.44 Hz, 1 H) 6.66 (s, 1 H) 6.56 (dd, J= 9.78, 1.10 Hz, 1 H) 5.35 (t, J = 5.87 Hz, 1 H) 4.07 (dd, J = 11.13,3.18 Hz, 1 H) 3.76-3.91 (m, 2 H) 3.44-3.70 (m, 4 H) 3.35 (dd, J = 10.64,3.06 Hz, 1 H) 2.81-3.07 (m, 3 H) 2.25 (s, 3 H).; LCMS (m/z) (M + H) =535.0, 1.46 min. 440

N-(3-((4aR,5S)- 5,7-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H) 9.37 (d, J = 1.83 Hz, 1 H) 9.18 (s, 1 H) 8.68 (s, 1 H) 7.52- 7.90 (m,2 H) 7.30 (d, J = 8.44 Hz, 1H) 6.66 (s, 1 H) 6.56 (dd, J = 9.72, 1.16Hz, 1 H) 5.35 (t, J = 5.87 Hz, 1 H) 4.06 (dd, J = 11.13, 3.06 Hz, 1 H)3.78-3.93 (m, 2 H) 3.44-3.68 (m, 4 H) 3.35 (dd, J = 10.51, 2.93 Hz, 1 H)2.79-3.07 (m, 3 H) 2.19-2.34 (m, 3 H).; LCMS (m/z) (M + H) = 534.1, 1.41min.

Example 441(rac)-N-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide

2-(trifluoromethyl)isonicotinic acid (1 equiv.),10-(5-amino-2-methylpyridin-3-yl)-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol(1.0 equiv.), EDC.HCl (1.2 equiv.), HOAT (1.2 equiv.) in DMF (0.1 M)were stirred at inert atmosphere for 1 h. The reaction mixture waspurified via reverse phase BASIC prep-HPLC to give the desired racemateand diastereomeric productN-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide(4%). ¹H NMR (400 MHz, Methanol-d4) δ 8.92 (d, J=5.0 Hz, 1H), 8.82 (d,J=2.5 Hz, 1H), 8.33 (s, 1H), 8.14 (dd, J=5.0, 1.3 Hz, 1H), 8.06 (d,J=2.5 Hz, 1H), 7.39 (dd, J=7.7, 0.8 Hz, 1H), 6.63 (dd, J=7.6, 1.5 Hz,1H), 6.56 (d, J=1.4 Hz, 1H), 4.81-4.78 (m, 1H), 3.99-3.67 (m, 6H),3.51-3.44 (m, 1H), 2.48 (s, 3H), 2.34-2.15 (m, 2H), 2.09-1.89 (m, 2H).LCMS (m/z) (M+H)=499.1, Rt=0.99 min.

Examples 442 and 443.N-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide

The following compounds were obtained from chiral SFC ofN-(5-(7-hydroxy-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-10-yl)-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide(NIQ120).

442

N-(5-((5aS,7R)- 7-hydroxy- 1,2,5,5a,6,7- hexahydro-4H- [1,4]oxazepino[4,5-a]quinolin- 10-yl)-6- methylpyridin- 3-yl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.92 (d, J = 5.0 Hz,1H), 8.82 (d, J = 2.5 Hz, 1H), 8.33 (s, 1H), 8.17-8.13 (m, 1H), 8.06 (d,J = 2.5 Hz, 1H), 7.39 (dd, J = 7.7, 0.8 Hz, 1H), 6.63 (dd, J = 7.6, 1.5Hz, 1H), 6.56 (d, J = 1.4 Hz, 1H), 4.82-4.80 (m, 1H), 3.97-3.68 (m, 6H),3.52-3.43 (m, 1H), 2.48 (s, 3H), 2.33-2.15 (m, 2H), 2.08-1.94 (m, 2H).LCMS (m/z) (M + H) = 499.1, Rt = 0.98 min. 443

N-(5-((5aS,7S)- 7-hydroxy- 1,2,5,5a,6,7- hexahydro-4H- [1,4]oxazepino[4,5-a]quinolin- 10-yl)-6- methylpyridin- 3-yl)-2- (trifluoromethyl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.92 (d, J = 5.0 Hz,1H), 8.82 (d, J = 2.5 Hz, 1H), 8.33 (s, 1H), 8.16-8.13 (m, 1H), 8.06 (d,J = 2.5 Hz, 1H), 7.39 (dd, J = 7.7, 0.8 Hz, 1H), 6.63 (dd, J = 7.6, 1.5Hz, 1H), 6.56 (d, J = 1.4 Hz, 1H), 4.82-4.79 (m, 1H), 3.95-3.69 (m, 6H),3.51-3.42 (m, 1H), 2.48 (s, 3H), 2.34-2.16 (m, 2H), 2.07-1.94 (m, 2H).LCMS (m/z) (M + H) = 499.1, Rt = 0.98 min.

The compounds listed in the table below, were prepared using methodssimilar to those described for the preparation of Example 441 above,using the appropriate starting materials:

444

2-(2- fluoropropan-2- yl)-N-(5- ((5aS,7R)-7- hydroxy- 1,2,5,5a,6,7-hexahydro-4H- [1,4|oxazepino [4,5-a]quinolin- 10-yl)-6- ¹H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.5 Hz, 1H), 8.71 (dt, J = 5.1, 0.9 Hz, 1H),8.09 (s, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.79 (dd, J = 5.1, 1.7 Hz, 1H),7.38 (dd, J = 7.7, 0.7 Hz, 1H), 6.63 (dd, J = 7.6, 1.5 Hz, 1H), 6.56 (d,J = 1.4 Hz, 1H), 4.83-4.78 (m, 1H), 3.94-3.71 (m, 6H), 3.52- 3.40 (m,1H), 2.47 (s, 3H), 2.33-2.15 (m, 2H), 2.07-1.94 (m, 2H), 1.76 (s,methylpyridin-3- 3H), 1.70 (s, 3H). LCMS (m/z) yl)isonicotinamide (M +H) = 491.3, Rt = 1.45 min. 445

2-(2- fluoropropan-2- yl)-N-(5- ((5aS,7S)-7- hydroxy- 1,2,5,5a,6,7-hexahydro-4H- [1,4]oxazepino [4,5-a]quinolin- 10-yl)-6- ¹H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.5 Hz, 1H), 8.70 (dt, J = 5.1, 0.8 Hz, 1H),8.09 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 5.1, 1.7 Hz, 1H),7.38 (dd, J = 7.7, 0.7 Hz, 1H), 6.62 (dd, J = 7.6, 1.5 Hz, 1H), 6.56 (d,J = 1.3 Hz, 1H), 4.83-4.79 (m, 1H), 3.93-3.74 (m, 6H), 3.52- 3.40 (m,1H), 2.47 (s, 3H), 2.34-2.14 (m, 2H), 2.07-1.93 (m, 2H), 1.75 (s,methylpyridin-3- 3H), 1.70 (s, 3H). LCMS (m/z) yl)isonicotinamide (M +H) = 491.3, Rt = 1.45 min. 446

N-(5-((5aS,7R)-7- hydroxy- 1,2,5,5a,6,7- hexahydro-4H- [1,4]oxazepino[4,5-a]quinolin- 10-yl)-6- methylpyridin-3- yl)-3-(trifluoro-methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.5 Hz,1H), 8.29 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H),7.94-7.87 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 0.8 Hz,1H), 6.63 (dd, J = 7.6, 1.5 Hz, 1H), 6.56 (d, J = 1.4 Hz, 1H), 4.83-4.79 (m, 1H), 3.94-3.71 (m, 6H), 3.52-3.42 (m, 1H), 2.47 (s, 3H), 2.34-2.14 (m, 2H), 2.08-1.91 (m, 2H). LCMS (m/z) (M + H) = 498.1, Rt = 1.05min. 447

N-(5-((5aS,7S)-7- hydroxy- 1,2,5,5a,6,7- hexahydro-4H- [1,4]oxazepino[4,5-a]quinolin- 10-yl)-6- methylpyridin-3- yl)-3-(trifluoro-methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.5 Hz,1H), 8.29 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H),7.94-7.88 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 0.8 Hz,1H), 6.63 (dd, J = 7.6, 1.5 Hz, 1H), 6.56 (d, J = 1.4 Hz, 1H), 4.83-4.80 (m, 1H), 3.93-3.74 (m, 6H), 3.53-3.42 (m, 1H), 2.47 (s, 3H), 2.35-2.15 (m, 2H), 2.08-1.92 (m, 2H). LCMS (m/z) (M + H) = 498.1, Rt = 1.05min.

Example 448N-(3-((4aS,5R)-5-(2-hydroxypropan-2-yl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A mixture of2-((4aS,5R)-9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)propan-2-ol(1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.1 equiv.), Xphos G2-Pd-Cy (0.05 equiv.), Xphos (0.05 equiv.) andK₃PO₄ (2 equiv., 0.5 M) in dioxane (0.13 M) was stirred at 70° C. blocktemperature for 1 hr. The reaction mixture was poured onto water andextracted with EtOAc. Organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (DCM with 0-30% MeOH)to give the desired final product,N-(3-((4aS,5R)-5-(2-hydroxypropan-2-yl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(74%). 1H NMR (400 MHz, Methanol-d4) δ 8.90 (d, J=5.0 Hz, 1H), 8.29 (s,1H), 8.11 (dd, J=5.0, 1.2 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.66 (dd,J=8.2, 2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.23(d, J=1.6 Hz, 1H), 4.20 (dd, J=11.8, 2.6 Hz, 1H), 4.03 (d, J=14.0 Hz,1H), 3.91 (dt, J=10.7, 3.1 Hz, 1H), 3.69-3.62 (m, 1H), 3.59-3.49 (m,2H), 3.46-3.37 (m, 1H), 3.03-2.94 (m, 2H), 2.27 (s, 3H), 2.15-2.05 (m,1H), 1.40 (s, 3H), 1.34 (s, 3H). LCMS (m/z) (M+H)=527.2, Rt=1.04 min.

The compounds listed in the table below, were prepared using methodssimilar to those described for the preparation of example 448 using theappropriate starting materials:

449

N-(5-((4aS,5R)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3-a] [1,5]naphthyridin- 9-yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83(d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.11 (d, J= 2.4 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.82-7.70 (m, 2H), 7.29 (d, J =1.6 Hz, 1H), 4.21 (dd, J = 11.8, 2.5 Hz, 1H), 4.05 (d, J = 14.0 Hz, 1H),3.92 (dt, J = 10.7, 3.1 Hz, 1H), 3.66 (dd, J = 11.1, 2.2 Hz, 1H),3.61-3.48 (m, 2H), 3.49-3.37 (m, 1H), 3.07-2.94 (m, 2H), 2.49 (s, 3H),2.17-2.04 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H). LCMS (m/z) (M + H) =527.2, Rt = 0.95 min. 450

2-(1,1- difluoroethyl)-N- (3-((4aS,5R)-5-(2- hydroxypropan-2-yl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5] naphthyridin-9-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.84-8.74 (m, 1H), 8.17 (s, 1H), 8.00- 7.92 (m, 1H), 7.73 (d, J = 1.6Hz, 1H), 7.65 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.31(d, J = 8.3 Hz, 1H), 7.23 (d, J = 1.5 Hz, 1H), 4.20 (dd, J = 11.7, 2.5Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H), 3.91 (dt, J = 10.7, 3.0 Hz, 1H),3.65 (dd, J = 11.1, 2.3 Hz, 1H), 3.60-3.49 (m, 2H), 3.46- 3.36 (m, 1H),3.06-2.92 (m, 2H), 2.27 (s, 3H), 2.15-1.97 (m, 4H), 1.40 (s, 3H), 1.34(s, 3H). LCMS (m/z) (M + H) = 523.2, Rt = 1.03 min. 451

N-(3-((4aR,5S)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5] naphthyridin-9- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.73(d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 4.20 (dd, J= 11.8, 2.6 Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H), 3.91 (dt, J = 10.7, 3.1Hz, 1H), 3.65 (dd, J = 11.1, 2.3 Hz, 1H), 3.59-3.48 (m, 2H), 3.47- 3.36(m, 1H), 3.06-2.93 (m, 2H), 2.27 (s, 3H), 2.16-2.05 (m, 1H), 1.40 (s,3H), 1.34 (s, 3H). LCMS (m/z) (M + H) = 527.2, Rt = 1.05 min. 452

N-(5-((4aR,5S)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5] naphthyridin-9- yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83(d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.12 (d, J= 2.5 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.81-7.70 (m, 2H), 7.29 (d, J =1.7 Hz, 1H), 4.21 (dd, J = 11.8, 2.6 Hz, 1H), 4.05 (d, J = 14.0 Hz, 1H),3.92 (dt, J = 10.7, 3.1 Hz, 1H), 3.66 (dd, J = 11.1, 2.2 Hz, 1H),3.60-3.49 (m, 2H), 3.48-3.37 (m, 1H), 3.07-2.94 (m, 2H), 2.49 (s, 3H),2.16-2.05 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H). LCMS (m/z) (M + H) =527.2 , Rt = 0.95 min. 453

2-(1,1- difluoroethyl)-N- (3-((4aR,5S)-5-(2- hydroxypropan-2-yl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5] naphthyridin-9-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.83-8.76 (m, 1H), 8.21-8.14 (m, 1H), 7.99-7.91 (m, 1H), 7.73 (d, J =1.7 Hz, 1H), 7.65 (dd, J = 8.2, 2.3 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H),7.31 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 4.20 (dd, J = 11.7,2.6 Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H), 3.90 (dt, J = 10.7, 3.1 Hz, 1H),3.65 (dd, J = 11.2, 2.3 Hz, 1H), 3.60-3.48 (m, 2H), 3.47- 3.35 (m, 1H),3.07-2.92 (m, 2H), 2.26 (s, 3H), 2.13-1.97 (m, 4H), 1.40 (s, 3H), 1.34(s, 3H). LCMS (m/z) (M + H) = 523.2, Rt = 1.03 min. 454

N-(3-((4aS,5S)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,41oxazino[4,3- a][l,5] naphthyridin-9- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H),7.80(d, J = 1.7 Hz, 1H), 7.70-7.59 (m, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.12(d, J = 1.6 Hz, 1H), 3.93 (dd, J = 11.1, 2.4 Hz, 2H), 3.76 (td, J =11.7, 2.5 Hz, 1H), 3.57 (d, J = 11.9 Hz, 1H), 3.47-3.39 (m, 1H),3.26-3.18 (m, 1H), 3.13 (td, J = 12.3, 3.5 Hz, 1H), 2.94-2.82 (m, 2H),2.25 (s, 3H), 1.88 (q, J = 5.3 Hz, 1H), 1.22 (s, 3H), 0.95 (s, 3H). LCMS(m/z) (M + H) = 527.2, Rt = 1.03 min. 455

N-(5-((4aS,5S)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][l,5] naphthyridin-9- yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83(d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.14 (d, J= 2.5 Hz, 1H), 7.94-7.89 (m, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.75 (t, J =7.8 Hz, 1H), 7.19 (d, J = 1.7 Hz, 1H), 3.93 (dd, J = 11.2, 2.2 Hz, 2H),3.76 (td, J = 11.7, 2.5 Hz, 1H), 3.61 (d, J = 11.7 Hz, 1H), 3.43 (t, J =10.8 Hz, 1H), 3.28-3.22 (m, 1H), 3.17 (dd, J = 12.3, 3.4 Hz, 1H), 2.90(t, J = 5.7 Hz, 2H), 2.47 (s, 3H), 1.95-1.82 (m, 1H), 1.22 (s, 3H), 0.97(s, 3H). LCMS (m/z) (M + H) = 527.2, Rt = 0.93 min. 456

2-(1,1- difluoroethyl)-N- (3-((4aS,5S)-5-(2- hydroxypropan-2-yl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5] naphthyridin-9-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.79 (d, 1H), 8.17 (s, 1H), 8.01-7.90 (m, 1H), 7.81 (d, J = 1.7 Hz, 1H),7.69-7.60 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H),3.93 (dd, J = 11.2, 2.8 Hz, 2H), 3.75 (td, J = 11.7, 2.5 Hz, 1H), 3.58(d, J = 11.8 Hz, 1H), 3.43 (t, J = 10.8 Hz, 1H), 3.26-3.19 (m, 1H), 3.13(td, J = 12.4, 3.4 Hz, 1H), 2.95-2.80 (m, 2H), 2.25 (s, 3H), 2.03 (t, J= 18.7 Hz, 3H), 1.88 (q, J = 5.3 Hz, 1H), 1.22 (s, 3H), 0.95 (s, 3H).LCMS (m/z) (M + H) = 523.2, Rt = 1.01 min. 457

N-(3-((4aR,5R)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,41oxazino[4,3- a][1,5] naphthyridin-9- yl)-4- methylphenyl)-2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.80(d, J = 1.7 Hz, 1H), 7.70-7.59 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.12(d, J = 1.6 Hz, 1H), 3.93 (dd, J = 11.2, 2.8 Hz, 2H), 3.75 (td, J =11.7, 2.5 Hz, 1H), 3.57 (d, J = 11.8 Hz, 1H), 3.43 (t, J = 10.8 Hz, 1H),3.25-3.18 (m, 1H), 3.13 (td, 12.3, 3.4 Hz, 1H), 2.94-2.81 (m, 2H), 2.25(s, 3H), 1.88 (q, J = 5.3 Hz, 1H), 1.22 (s, 3H), 0.95 (s, 3H). LCMS(m/z) (M + H) = 527.2, Rt = 1.03 min. 458

N-(5-((4aR,5R)-5- (2- hydroxypropan-2- yl)-1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5] naphthyridin-9- yl)-6- methylpyridin-3-yl)-3-(trifluoro- methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83(d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.14 (d, J= 2.5 Hz, 1H), 7.93-7.90 (m, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.74 (t, J =7.8 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 3.93 (dd, J = 11.1, 2.3 Hz, 2H),3.76 (td, J = 11.7, 2.5 Hz, 1H), 3.60 (d, J = 11.8 Hz, 1H), 3.43 (t, J =10.8 Hz, 1H), 3.28-3.21 (m, 1H), 3.20-3.10 (m, 1H), 2.96-2.83 (m, 2H),2.47 (s, 3H), 1.88 (q, J = 5.2 Hz, 1H), 1.22 (s, 3H), 0.97 (s, 3H). LCMS(m/z) (M + H) = 527.2, Rt = 0.94 min. 459

2-(1,1- difluoroethyl)-N- (3-((4aS,5S)-5-(2- hydroxypropan-2-yl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5] naphthyridin-9-yl)-4- methylphenyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.84-8.74 (m, 1H), 8.17 (s, 1H), 8.00- 7.91 (m, 1H), 7.80 (d, J = 1.7Hz, 1H), 7.70-7.56 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 1.6Hz, 1H), 3.93 (dd, J = 11.3, 2.8 Hz, 2H), 3.75 (td, J = 11.7, 2.5 Hz,1H), 3.57 (d, J = 11.9 Hz, 1H), 3.47-3.38 (m, 1H), 3.25-3.18 (m, 1H),3.13 (td, J = 12.3, 3.4 Hz, 1H), 2.94-2.82 (m, 2H), 2.25 (s, 3H), 2.03(t, J = 18.7 Hz, 3H), 1.87 (q, J = 5.3 Hz, 1H), 1.22 (s, 3H), 0.95 (s,3H). LCMS (m/z) (M + H) = 523.2, Rt = 1.01 min.

Intermediate for Example 467.5-(5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-amine

A mixture of9-bromo-5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline(1 equiv.),6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(1.1 equiv.), Xphos G2-Pd-Cy (0.05 equiv.), Xphos (0.05 equiv.) andK₃PO₄ (2 equiv., 0.5 M) in dioxane (0.16 M) was stirred at 70° C. blocktemperature for 1 hr. The reaction mixture was poured onto water andextracted with EtOAc. Organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (heptane with 0-60%ethyl acetate) to give the desired product,3-(5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylaniline(98%). LCMS (m/z) (M+H)=346.1, Rt=0.91 min.

Intermediate for Example 469.3-(5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylaniline

Step 1:

To a solution of(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol(1.0 equiv.) in THF (0.12 M) was added triethylamine (12 equiv.)followed by perfluorobutanesulfonyl fluoride (4 equiv.) andtriethylamine trihydrofluoride (4 equiv.). The reaction mixture wasstirred at 60° C. block temperature for 18 hr. The reaction mixture waspoured onto water and extracted with EtOAc. Organic phase was washedwith brine, dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified by flash chromatography over silica gel(heptane with 0 to 100% ethyl acetate) to give the desired product,9-bromo-5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline(98%). LCMS (m/z) (M+H)=319.9, Rt=1.51 min.

Step 2:

A mixture of9-bromo-5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline(1 equiv.),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.1equiv.), Xphos G2-Pd-Cy (0.05 equiv.), Xphos (0.05 equiv.) and K₃PO₄ (2equiv., 0.5 M) in dioxane (0.16 M) was stirred at 70° C. blocktemperature for 1 hr. The reaction mixture was poured onto water andextracted with EtOAc. Organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (heptane with 0-60%ethyl acetate) to give the desired product,3-(5-fluoro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylaniline(100%). LCMS (m/z) (M+H)=345.1, Rt=1.03 min.

The compounds listed in the table below, were prepared using theintermediates described above and appropriate starting materials:

467

2-(1,1- difluoromethyl)-N- (5-((4aS,5S)-5- fluoro-5- (fluoromethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6-methylpyridin-3- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d6) δ8.85-8.79 (m, 2H), 8.24-8.19 (m, 1H), 8.09 (d, J = 2.5 Hz, 1H), 8.02-7.93 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 1.3 Hz, 1H), 6.83(dd, J = 7.6, 1.5 Hz, 1H), 4.62-4.34 (m, 2H), 4.01 (dd, J = 11.5, 3.1Hz, 1H), 3.97-3.88 (m, 1H), 3.79-3.61 (m, 3H), 3.26-3.19 (m, 1H), 3.16-2.95 (m, 3H), 2.48 (s, 3H), 2.04 (t, J = 18.7 Hz, 3H). LCMS (m/z) (M +H) = 515.3, Rt = 1.33 min 468

2-(tert-butyl)-N-(5- ((4aS,5S)-5-fluoro- 5-(fluoromethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3-yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.5 Hz,1H), 8.67 (dd, J = 5.1, 0.8 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.94 (dd,J = 1.5, 0.8 Hz, 1H), 7.68 (dd, J = 5.1, 1.6 Hz, 1H), 7.19 (d, J = 7.6Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 6.83 (dd, J = 7.5, 1.5 Hz, 1H),4.63-4.30 (m, 2H), 4.01 (dd, J = 11.5, 3.1 Hz, 1H), 3.97- 3.90 (m, 1H),3.78-3.62 (m, 3H), 3.26-3.19 (m, 1H), 3.16-2.95 (m, 3H), 2.48 (s, 3H),1.42 (s, 9H). LCMS (m/z) (M + H) = 507.1, Rt = 1.10 min. 469

N-(3-((4aS,5S)-5- fluoro-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-5- (trifluorometh-yl)nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.33 (d, J = 1.9 Hz,1H), 9.06 (d, J = 1.2 Hz, 1H), 8.64 (s, 1H), 7.67-7.52 (m, 2H), 7.27 (d,J = 8.1 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.79 (dd, J =7.5, 1.5 Hz, 1H), 4.59- 4.31 (m, 2H), 4.00 (dd, J = 11.5, 3.1 Hz, 1H),3.92 (dd, J = 11.2, 3.5 Hz, 1H), 3.74-3.61 (m, 3H), 3.23-2.93 (m, 4H),2.25 (s, 3H). LCMS (m/z) (M + H) = 518.1, Rt = 1.65 min. 470

N-(5-((4aS,5S)-5- fluoro-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-5-(trifluorometh- yl)nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.36 (d,J = 2.0 Hz, 1H), 9.12-9.02 (m, 1H), 8.80 (d, J = 2.5 Hz, 1H), 8.68 (td,J = 2.1, 0.7 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 7.6 Hz,1H), 6.87 (d, J = 1.3 Hz, 1H), 6.83 (dd, J = 7.6, 1.5 Hz, 1H), 4.62-4.33 (m, 2H), 4.01 (dd, J = 11.5, 3.1 Hz, 1H), 3.97-3.88 (m, 1H), 3.77-3.62 (m, 3H), 3.28-2.96 (m, 4H), 2.47 (s, 3H). LCMS (m/z) (M + H) =519.1, Rt = 1.13 min. 471

N-(5-((4aS,5S)-5- fluoro-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-6- methylpyridin-3- yl)-2-(trifluoromethyl)iso- nictonamide ¹H NMR (400 MHz, Methanol-d4) δ 8.92(d, J = 5.0 Hz, 1H), 8.82 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 8.14 (dd, J= 5.0, 1.2 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H),6.87 (s, 1H), 6.83 (dd, J = 7.6, 1.5 Hz, 1H), 4.62-4.32 (m, 2H), 4.01(dd, J = 11.5, 3.1 Hz, 1H), 3.97-3.87 (m, 1H), 3.77-3.61 (m, 3H),3.28-2.95 (m, 4H), 2.48 (s, 3H). LCMS (m/z) (M + H) = 519.0, Rt = 1.16min. 472

N-(3-((4aS,5S)-5- fluoro-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89(d, J = 5.0 Hz, 1H), 8.28 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.67-7.52 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.82(s, 1H), 6.79 (dd, J = 7.5, 1.5 Hz, 1H), 4.62-4.29 (m, 2H), 4.00 (dd, J= 11.5, 3.1 Hz, 1H), 3.92 (dd, J = 11.2, 3.5 Hz, 1H), 3.77-3.61 (m, 3H),3.24-2.93 (m, 4H), 2.25 (s, 3H). LCMS (m/z) (M + H) = 518.1, Rt = 1.66min. 473

2-(1,1- difluoromethyl)-N- (3-((4aS,5S)-5- fluoro-5- (fluoromethyl)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.82-8.73(m, 1H), 8.16 (s, 1H), 7.97-7.91 (m, 1H), 7.67-7.52 (m, 2H), 7.32 (d, J= 7.5 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.07(s, 1H), 6.82 (s, 1H), 6.78 (dd, J = 7.5, 1.4 Hz, 1H), 4.61- 4.27 (m,2H), 4.00 (dd, J = 11.5, 3.1 Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H),3.75-3.62 (m, 3H), 3.23-2.92 (m, 4H), 2.24 (s, 3H), 2.02 (t, J = 18.7Hz, 3H). LCMS (m/z) (M + H) = 514.1, Rt = 1.63 min. 474

2-(tert-butyl)-N-(3- ((4aS,5S)-5-fluoro- 5-(fluoromethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)iso-nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.63 (dd, J = 5.1, 0.8 Hz,1H), 7.90 (s, 1H), 7.64 (dd, J = 5.1, 1.6 Hz, 1H), 7.61-7.51 (m, 2H),7.26 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.79(dd, J = 7.5, 1.4 Hz, 1H), 4.60-4.27 (m, 2H), 4.00 (dd, J = 11.5, 3.1Hz, 1H), 3.91 (dd, J = 11.2, 3.5 Hz, 1H), 3.75-3.61 (m, 3H), 3.23-2.92(m, 4H), 2.24 (s, 3H), 1.41 (s, 9H). LCMS (m/z) (M + H) = 506.3, Rt =1.47 min. 475

N-(3-((4aS,5S)-5- fluoro-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a]quinolin-9-yl)-4- methylphenyl)-6- (trifluorometh-yl)pyridazine-4- carboxamide ¹H NMR (400 MHz, Methanol-d4) δ 9.85 (d, J= 2.0 Hz, 1H), 8.57 (s, 1H), 7.69-7.54 (m, 2H), 7.28 (d, J = 8.2 Hz,1H), 7.14 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.78 (dd, J = 7.5, 1.5 Hz,1H), 4.59-4.32 (m, 2H), 4.00 (dd, J = 11.5, 3.1 Hz, 1H), 3.92 (dd, J =11.2, 3.5 Hz, 1H), 3.75-3.62 (m, 3H), 3.25-2.93 (m, 4H), 2.25 (s, 3H).LCMS (m/z) (M + H) = 519.1, Rt = 1.60 min.

Intermediate for Ex. 476.(9-bromo-5,8-difluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol

(9-bromo-5,8-difluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanolwas synthesized using the same procedure as for synthesis of Example369, starting with 4-bromo-2,5-difluorobenzaldehyde staring material.The desired final intermediate was used after its chiral separation to 4pure single enantiomers and diastereomers.

The compounds listed in the table below were prepared using the aboveintermediate and the appropriate starting materials:

476

N-(3-((4aR,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 2-(1,1-difluoroethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.83-8.74 (m, 1H), 8.17 (s, 1H), 7.99- 7.90 (m, 1H), 7.64 (dd, J = 8.2,2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.93(d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J = 11.5, 3.2Hz, 1H), 3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.74-3.53 (m, 5H), 3.23-3.08(m, 2H), 3.02-2.84 (m, 2H), 2.18 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H).LCMS (m/z) (M + H) = 530.1, Rt = 1.45 min. 477

N-(3-((4aR,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz,Methanol-d4) δ 9.86 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 7.67(dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 8.3Hz, 1H), 6.94 (d, J = 9.6 Hz, 1H), 6.71 (d, J = 6.3 Hz, 1H), 4.06 (dd, J= 11.5, 3.2 Hz, 1H), 3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.73-3.53 (m, 5H),3.22- 3.09 (m, 2H), 3.02-2.86 (m, 2H), 2.18 (s, 3H). LCMS (m/z) (M + H)= 535.1, Rt = 1.42 min. 478

N-(3-((4aR,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.68(d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.75 (dd, J = 5.1, 1.7 Hz, 1H), 7.63(dd, J = 8.2, 2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 8.3Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J= 11.5, 3.2 Hz, 1H), 3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.75- 3.51 (m,5H), 3.22-3.07 (m, 2H), 3.01- 2.85 (m, 2H), 2.17 (s, 3H), 1.75 (s, 3H),1.69 (s, 3H). LCMS (m/z) (M + H) = 526.2, Rt = 1.45 min. 479

N-(5-((4aR,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 6-methylpyridin- 3-yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J =2.5 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 2.5Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 6.99 (d, J= 9.6 Hz, 1H), 6.78 (d, J = 6.3 Hz, 1H), 4.07 (dd, J = 11.4, 3.2 Hz,1H), 3.96-3.87 (m, 1H), 3.73-3.55 (m, 5H), 3.24- 3.12 (m, 2H), 3.03-2.89(m, 2H), 2.40 (s, 3H). LCMS (m/z) (M + H) = 534.0, Rt = 1.13 min. 480

N-(3-((4aR,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.65(dd, J = 8.2, 2.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.3Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J= 11.5, 3.2 Hz, 1H), 3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.75- 3.51 (m,5H), 3.23-3.08 (m, 2H), 3.02- 2.86 (m, 2H), 2.18 (s, 3H). LCMS (m/z)(M + H) = 534.1, Rt = 1.48 min. 481

N-(3-((4aS,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 2-(1,1-difluoroethyl)iso- nicotinamide 1H NMR (400 MHz, Methanol-d4) δ8.85-8.69 (m, 1H), 8.17 (s, 1H), 8.02- 7.89 (m, 1H), 7.64 (dd, J = 8.2,2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.93(d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J = 11.4, 3.2Hz, 1H), 3.91 (dd, J = 11.2, 3.6 Hz, 1H), 3.73-3.53 (m, 5H), 3.22-3.08(m, 2H), 3.01-2.86 (m, 2H), 2.18 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H).LCMS (m/z) (M + H) = 530.1 Rt = 1.45 min. 482

N-(3-((4aS,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 6-(trifluoromethyl) pyridazine-4- carboxamide ¹H NMR (400 MHz,Methanol-d4) δ 9.86 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 7.67(dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.3Hz, 1H), 6.94 (d, J = 9.6 Hz, 1H), 6.71 (d, J = 6.3 Hz, 1H), 4.06 (dd, J= 11.5, 3.2 Hz, 1H), 3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.74-3.53 (m, 5H),3.22- 3.10 (m, 2H), 3.01-2.87 (m, 2H), 2.18 (s, 3H). LCMS (m/z) (M + H)= 535.1, Rt = 1.42 min. 483

N-(3-((4aS,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 2-(2-fluoropropan-2- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.68(d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.76 (dd, J = 5.1, 1.6 Hz, 1H), 7.63(dd, J = 8.2, 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 8.3Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J= 11.2, 3.4 Hz, 1H), 3.91 (dd, J = 11.4, 3.3 Hz, 1H), 3.74- 3.54 (m,5H), 3.23-3.08 (m, 2H), 3.00- 2.86 (m, 2H), 2.17 (s, 3H), 1.75 (s, 3H),1.70 (s, 3H). LCMS (m/z) (M + H) = 526.2, Rt = 1.45 min. 484

N-(5-((4aS,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 6-methylpyridin- 3-yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J =2.5 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 2.5Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.00 (d, J= 9.6 Hz, 1H), 6.78 (d, J = 6.3 Hz, 1H), 4.07 (dd, J = 11.5, 3.2 Hz,1H), 3.92 (d, J = 11.5 Hz, 1H), 3.73-3.54 (m, 5H), 3.24- 3.13 (m, 2H),3.03-2.89 (m, 2H), 2.40 (s, 3H). LCMS (m/z) (M + H) = 534.1, Rt = 1.13min. 485

N-(3-((4aS,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 2-(trifluoromethyl) isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.65(dd, J = 8.2, 2.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.3Hz, 1H), 6.94 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J= 11.5, 3.2 Hz, 1H), 3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.75- 3.53 (m,5H), 3.22-3.10 (m, 2H), 3.02- 2.86 (m, 2H), 2.18 (s, 3H). LCMS (m/z)(M + H) = 534.1, Rt = 1.48 min. 486

N-(3-((4aS,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.33 (d,J = 1.8 Hz, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 7.64 (dd, J = 8.2, 2.3 Hz,1H), 7.58 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.93 (d, J =9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.10-4.02 (m, 1H), 3.91 (dd, J =11.4, 3.4 Hz, 1H), 3.74-3.53 (m, 5H), 3.23-3.07 (m, 2H), 3.01-2.85 (m,2H), 2.18 (s, 3H). LCMS (m/z) (M + H) = 534.1, Rt = 1.45 min. 487

N-(3-((4aS,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.33 (d,J = 1.8 Hz, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 7.63 (dd, J = 8.2, 2.3 Hz,1H), 7.58 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.89 (d, J =9.7 Hz, 1H), 6.74 (d, J = 6.4 Hz, 1H), 4.07 (dd, J = 10.9, 2.5 Hz, 1H),3.93-3.53 (m, 6H), 3.43 (td, J = 10.7, 2.8 Hz, 1H), 3.19 (t, J = 15.6Hz, 1H), 3.04-2.89 (m, 2H), 2.17 (s, 3H). LCMS (m/z) (M + H) = 534.1, Rt= 1.45 min. 488

N-(3-((4aR,5R)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.33 (d,J = 1.8 Hz, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 7.64 (dd, J = 8.2, 2.3 Hz,1H), 7.58 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.93 (d, J =9.6 Hz, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.06 (dd, J = 11.2, 3.5 Hz, 1H),3.91 (dd, J = 11.4, 3.4 Hz, 1H), 3.73-3.52 (m, 5H), 3.22- 3.08 (m, 2H),3.00-2.86 (m, 2H), 2.18 (s, 3H). LCMS (m/z) (M + H) = 534.1, Rt = 1.45min. 489

N-(3-((4aR,5S)- 5,8-difluoro-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a]quinolin-9-yl)- 4-methylphenyl)- 5-(trifluoromethyl) nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 9.33 (d,J = 1.8 Hz, 1H), 9.06 (s, 1H), 8.64 (s, 1H), 7.63 (dd, J = 8.2, 2.3 Hz,1H), 7.58 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.89 (d, J =9.7 Hz, 1H), 6.74 (d, J = 6.3 Hz, 1H), 4.07 (dd, J = 11.0, 2.7 Hz, 1H),3.89 (dd, J = 11.3, 3.4 Hz, 1H), 3.87-3.54 (m, 5H), 3.43 (td, J = 10.7,2.9 Hz, 1H), 3.19 (t, J = 15.6 Hz, 1H), 3.04-2.91 (m, 2H), 2.17 (s, 3H).LCMS (m/z) (M + H) = 534.1, Rt = 1.45 min.

The compounds listed in the table below, were prepared usingintermediates described above and the appropriate starting materials:

490

N-(5-((4aR,5S)-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3-yl)- 3 -(trifluoro- methyl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.84 (d, J= 2.4 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 2.4Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.75 (t, J= 7.8 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 3.96-3.87 (m, 2H), 3.83-3.76(m, 2H), 3.73-3.62 (m, 2H), 3.55-3.46 (m, 2H), 3.14- 2.96 (m, 3H), 2.48(s, 3H), 2.32- 2.25 (m, 1H). LCMS (m/z) (M + H) = 499.1, Rt = 0.90 min.491

N-(3-((4aR,5S)-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methyphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.80(d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.2, 2.3 Hz, 1H), 7.62 (d, J = 2.2Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 3.91 (td, J= 11.6, 11.1, 3.2 Hz, 2H), 3.81- 3.75 (m, 2H), 3.73-3.61 (m, 2H),3.54-3.43 (m, 2H), 3.11-2.94 (m, 3H), 2.32-2.23 (m, 4H). LCMS (m/z) (M +H) = 499.1, Rt = 1.00 min. 492

2-(1,1- difluoroethyl)-N-(3- ((4aR,5S)-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.79 (d,1H), 8.17 (d, J = 5.0 Hz 1H), 7.95 (s, 1H), 7.81 (d, J = 1.7 Hz, 1H),7.65 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.32 (d, J =8.3 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 3.91 (td, J = 10.8, 3.2 Hz, 2H),3.82-3.76 (m, 2H), 3.74- 3.61 (m, 2H), 3.55-3.43 (m, 2H), 3.11-2.93 (m,3H), 2.32-2.24 (m, 4H), 2.03 (t, J = 18.7 Hz, 3H). LCMS (m/z) (M + H) =495.2, Rt = 0.97 min. 493

N-(5-((4aS,5R)-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3-yl)- 3-(trifluorometh- yl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J= 2.5 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 2.5Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.74 (t, J= 7.8 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 3.95-3.88 (m, 2H), 3.84-3.76(m, 2H), 3.73-3.62 (m, 2H), 3.55-3.45 (m, 2H), 3.13- 2.96 (m, 3H), 2.48(s, 3H), 2.33- 2.24 (m, 1H). LCMS (m/z) (M + H) = 499.1, Rt = 0.89 min.494

N-(3-((4aS,5R)-5- (hydroxymethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methyphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.80(d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.2, 2.3 Hz, 1H), 7.62 (d, J = 2.2Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 3.91 (td, J= 11.6, 11.1, 3.2 Hz, 2H), 3.82- 3.76 (m, 2H), 3.74-3.61 (m, 2H),3.55-3.43 (m, 2H), 3.11-2.94 (m, 3H), 2.32-2.23 (m, 4H). LCMS (m/z) (M +H) = 499.1, Rt = 0.99 min. 495

2-(1,1- difluoroethyl)-N-(3- ((4aS,5R)-5- (hydroxymethyl)- 1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4, δ 8.79 (d,J = 5.0 Hz, 1H), 8.17 (s, 1H), 7.95 (dd, J = 5.1, 1.5 Hz, 1H), 7.81 (d,J = 1.7 Hz, 1H), 7.65 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.2 Hz,1H), 7.31 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 3.90 (td, J =11.6, 11.1, 3.3 Hz, 2H), 3.82- 3.75 (m, 2H), 3.74-3.60 (m, 2H),3.55-3.42 (m, 2H), 3.11-2.93 (m, 3H), 2.32-2.22 (m, 4H), 2.03 (t, J =18.7 Hz, 3H). LCMS (m/z) (M + H) = 495.2, Rt = 0.97 min.

Intermediate for Example 496

Step 1:

Methyl 2-(morpholin-3-yl)acetate (1.034 g, 6.50 mmol),4-bromo-2-fluorobenzonitrile (1.186 g, 5.9 mmol), DIEA (3.09 ml, 17.70mmol) were combined in NMP (Volume: 5 ml) and the mixture heated in aheating block maintained at 110° C. for 24 h. After the elapsed time,the reaction mixture was diluted with EtOAc and washed with water twiceand then dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified by flash chromatography (0-50% EtOAc/heptane) to afford thedesired product methyl2-(4-(5-bromo-2-cyanopyridin-3-yl)morpholin-3-yl)acetate in 36% isolatedyield. LCMS (m/z) (M+H) 342.1; Rt.=0.0.92 min.

Step 2:

methyl 2-(4-(5-bromo-2-cyanopyridin-3-yl)morpholin-3-yl)acetate (715 mg,2.102 mmol) was dissolved in THF (5.2 mL), MeOH (3.5 mL) and thenLiOH.H₂O (441 mg, 10.51 mmol) dissolved in Water (1.7 mL)) was added.The mixture was agitated at room temperature for 1 h and thenconcentrated in vacuo. The residue was acidified to pH 4 and thenextracted with EtOAc. The combined organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue2-(4-(5-bromo-2-cyanopyridin-3-yl)morpholin-3-yl)acetic acid was takento the next step as such without any further purification. LCMS (m/z)(M+H) 325.9; Rt.=0.73 min.

Step 3: 2-(4-(5-bromo-2-cyanopyridin-3-yl)morpholin-3-yl)acetic acid(686 mg, 2.102 mmol) was dissolved in t-BuOH (21 mL)) and thentriethylamine (586 μl, 4.20 mmol) followed by DPPA (578 mg, 2.102 mmol)were added. The mixture was agitated at 90° C. overnight. The nextmorning, the reaction mixture was concentrated in vacuo and the residuewas purified by flash chromatography (0-40% EtOAc/heptane) to affordtert-butyl((4-(5-bromo-2-cyanopyridin-3-yl)morpholin-3-yl)methyl)carbamate in 45%isolated yield. LCMS (m/z) (M+H) 398.9; Rt.=1.04 min.

Step 4:

Tert-butyl((4-(5-bromo-2-cyanopyridin-3-yl)morpholin-3-yl)methyl)carbamate (374mg, 0.941 mmol) was dissolved in DCM (4.7 mL) and at room temperaturewas treated with 4 N HCl in dioxane (4.7 mL). The mixture was agitatedat room temperature for 1 h upon the reaction mixture was concentratedin vacuo and the residue3-(3-(aminomethyl)morpholino)-5-bromopicolinonitrile was taken to thenext step as such. LCMS (m/z) (M+H) 299.2; Rt.=0.70 min.

Step 5:

3-(3-(aminomethyl)morpholino)-5-bromopicolinonitrile (3.26 g, 9.77 mmol)was dissolved in EtOH (26 mL) and then NaOH (3.91 g, 98 mmol) was added.The mixture was placed in a preheated oil bath maintained at 100° C.After 10 min, the reaction mixture was cooled to room temperature andquenched by addition of 4N HCl (aq) until pH=1. The entire mixture wasextracted with EtOAc. The aq. acidic layer was then directly loaded ontoreverse-phase column and the product eluted with (0-30% ACN/water) andthe product fractions were collected and frozen and lyophilized toafford 530 mg of the desired product10-bromo-4,4a,5,6-tetrahydro-1H-[1,4]oxazino[4,3-a]pyrido[2,3-f][1,4]diazepin-7(2H)-one.LCMS (m/z) (M+H) 299.5; Rt.=0.55 min.

Step 6:

To an ice cold solution of10-bromo-1,2,4,4a,5,6-hexahydro-7H-[1,4]oxazino[4,3-a]pyrido[2,3-f][1,4]diazepin-7-one(1.0 equiv.) in DMF (0.34 M) was added NaH (2.5 equiv.) and stirred for1 hr. Bromoethane (2.5 equiv.) was then added and allowed the reactionmixture to come to ambient temperature. The reaction mixture was stirredfor 3 hr, quenched with water and extracted with EtOAc. The organicphase was washed with sat. NaHCO₃. The combined aqueous layer was backextracted with EtOAc. The combined organic phase was washed with brine,dried over sodium sulfate, filtered, and concentrated. The crude productwas purified by flash chromatography over silica gel (DCM with 0-10%MeOH) to give10-bromo-6-ethyl-1,2,4,4a,5,6-hexahydro-7H-[1,4]oxazino[4,3-a]pyrido[2,3-f][1,4]diazepin-7-onein 26% yield and the racemate material was resolved by chiral SFC. Twopeaks were isolated after chiral separation. LCMS (m/z) (M+H)=328.0,Rt=0.91 min.

The compounds listed in the table below were prepared using the aboveintermediate and the appropriate starting materials:

496

(S)-N-(3-(6-ethyl- 7-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-a]pyrido[2,3- f][1,4]diazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 8.12 (dd, J = 5.0, 1.2Hz, 1H), 7.73-7.66 (m, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 7.9Hz, 1H), 4.11 (dq, J = 14.2, 7.1 Hz, 1H), 3.92 (ddd, J = 18.5, 11.0, 2.4Hz, 2H), 3.76- 3.63 (m, 3H), 3.39-3.33 (m, 2H), 3.23-3.12 (m, 2H), 2.30(s, 3H), 1.26 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 526.1, Rt = 1.21min. 497

(S)-N-(5-(6-ethyl- 7-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-a]pyrido[2,3- f][1,4]diazepin- 10-yl)-6- methylpyridin-3- yl)-3-(trifluoromethyl) benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J =2.5 Hz, 1H), 8.35-8.28 (m, 2H), 8.24 (d, J = 7.9 Hz, 1H), 8.21 (d, J =2.4 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.58(d, J = 1.7 Hz, 1H), 4.11 (dq, J = 14.2, 7.1 Hz, 1H), 3.92 (ddd, J =18.4, 11.0, 2.3 Hz, 2H), 3.77-3.63 (m, 3H), 3.40- 3.32 (m, 3H),3.25-3.14 (m, 2H), 2.51 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). LCMS (m/z)(M + H) = 526.1, Rt = 1.02 min. 498

(S)-2-(1,1- difluoroethyl)-N- (3-(6-ethyl-7-oxo- 1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3- a]pyrido[2,3- f][1,4]diazepin- 10-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.80 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.21-8.15 (m, 1H), 7.96 (d, J = 5.0 Hz,1H), 7.74-7.64 (m, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 7.9 Hz,1H), 4.11 (dq, J = 14.2, 7.2 Hz, 1H), 3.92 (ddd, J = 18.9, 10.9, 2.4 Hz,2H), 3.76-3.63 (m, 3H), 3.40-3.32 (m, 3H), 3.23-3.12 (m, 2H), 2.30 (s,3H), 2.03 (t, J = 18.7 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H). LCMS (m/z)(M + H) = 522.1, Rt = 1.17 min. 499

(S)-N-(3-(6-ethyl- 7-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-a]pyrido[2,3- f][1,4]diazepin- 10-yl)-4- methyplhenyl)-3- fluoro-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.65(d, J = 4.7 Hz, 1H), 8.25 (d, J = 1.4 Hz, 1H), 7.95 (t, J = 4.8 Hz, 1H),7.66 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.2, 2.3 Hz, 1H), 7.50 (d, J =1.7 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 4.11 (dq, J = 14.1, 7.1 Hz, 1H),3.92 (ddd, J = 18.8, 11.0, 2.5 Hz, 2H), 3.76-3.63 (m, 3H), 3.38-3.32 (m,3H), 3.22- 3.14 (m, 2H), 2.29 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). LCMS(m/z) (M + H) = 544.1, Rt = 1.23 min. 500

(R)-N-(3-(6- ethyl-7-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-a]pyrido[2,3- f][1,4]diazepin- 10-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, MeOH-d4) δ ppm 10.73(s, 1 H) 9.00 (d, J = 5.01 Hz, 1 H) 8.37 (s, 1 H) 8.25 (d, J = 1.83 Hz,1 H) 8.20 (dd, J = 5.01, 1.10 Hz, 1H) 7.76 (dd, J = 8.25, 2.26 Hz, 1 H)7.72 (d, J = 2.20 Hz, 1 H) 7.36-7.43 (m, 2 H) 3.78-4.11 (m, 3 H) 3.44-3.70 (m, 3 H) 3.02-3.30 (m, 4 H) 2.26 (s, 3 H) 1.14 (t, J = 7.09 Hz, 3H) LCMS (m/z) (M + H) = 526.1, 1.21 min. 501

(R)-N-(5-(6- ethyl-7-oxo- 1,2,4a,5,6,7- hexahydro-4H- [1,4]oxazino[4,3-a]pyrido[2,3- f][1,4]diazepin- 10-yl)-6- methypyridin-3- yl)-3-(trifluoro- ¹H NMR (400 MHz, MeOH-d4) δ ppm 10.31-10.60 (m, 1 H) 8.75(d, J = 5.01 Hz, 1 H) 8.02 (s, 1 H) 7.82 (dd, J = 5.01, 1.59 Hz, 1 H)7.54-7.74 (m, 2 H) 7.27 (d, J = 8.31 Hz, 1 H) 5.63 ( d, J = 1.59 Hz, 1H) 5.54 (d, J = 1.47 Hz, 1 H) 3.95 (t, J = 5.81 Hz, 2 H) 3.76-3.89 (m, 2H) 3.63 (br d, J = 12.96 Hz, 1 H) 3.53 (td, J = 11.68, 2.57 Hz, 1 H)3.33-3.40 (m, 1 H) 3.21-3.29 (m, 1 H) 3.07 (td, methyl)benzamide J =12.35, 3.42 Hz, 1 H) 2.26 (s, 3 H) 1.93-2.13 (m, 1H) 1.74 (s, 3 H) 1.68(s, 3 H) 1.56-1.66 (m, 1 H).; LCMS (m/z) (M + H) = 526.1, 1.01 min. 502

(R)-2-(1,1- difluoroethyl)-N- (3-(6-ethyl-7- oxo-1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3- a]pyrido[2,3- f][1,4]diazepin- 10-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, MeOH-d4) δ ppm 8.80 (d,J = 5.0 Hz, 1 H), 8.26 (s, 1H), 8.21-8.15 (m, 1H), 7.96 (d, J = 5.0 Hz,1H), 7.74-7.64 (m, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 7.9 Hz,1H), 4.11 (dq, J = 14.2, 7.2 Hz, 1H), 3.92 (ddd, J = 18.9, 10.9, 2.4 Hz,2H), 3.76-3.63 (m, 3H), 3.40-3.32 (m, 3H), 3.23-3.12 (m, 2H), 2.30 (s,3H), 2.03 (t, J = 18.7 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).; LCMS (m/z)(M + H) = 522.2, 1.17 min. 503

(R)-2-(1,1- difluoroethyl)-N- (3-(6-ethyl-7- oxo-1,2,4a,5,6,7-hexahydro-4H- [1,4]oxazino[4,3- a]pyrido[2,3- f][1,4]diazepin- 10-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, MeOH-d4) δ ppm 8.65 (d,J = 4.7 Hz, 1H), 8.25 (d, J = 1.4 Hz, 1H), 7.95 (t, J = 4.8 Hz, 1H),7.66 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.2, 2.3 Hz, 1H), 7.50 (d, J =1.7 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 4.11 (dq, J = 14.1, 7.1 Hz, 1H),3.92 (ddd, J = 18.8, 11.0, 2.5 Hz, 2H), 3.76-3.63 (m, 3H), 3.38-3.32 (m,3H), 3.22-3.14 (m, 2H), 2.29 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).; LCMS(m/z) (M + H) = 544.1, 1.23 min.

The compounds listed in the table below were prepared using methodssimilar to those described for the preparation of Example 496 using theappropriate starting materials:

504

(S)-N-(3-(7-ethyl-8- oxo-1,2,4,5,5a,6,7,8- octahydropyrido[2′,3′:6,7][1,4]diazepino [1,2- d][1,4]oxazepin-11- yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 8.12 (dd, J= 5.0, 1.2 Hz, 1H), 7.74-7.65 (m, 2H), 7.37 (d, J = 9.1 Hz, 1H), 4.52(dd, J = 14.0, 3.7 Hz, 1H), 4.13-4.00 (m, 3H), 3.59 (t, J = 11.3 Hz,1H), 3.53-3.38 (m, 4H), 3.19-3.07 (m, 2H), 2.30 (s, 3H), 2.19-1.97 (m,2H), 1.21 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) = 540.1, Rt = 1.09min. 505

(R)-N-(3-(7-ethyl-8- oxo-1,2,4,5,5a,6,7,8- octahydropyrido[2′,3′:6,7][1,4]diazepino [1,2- d][1,4]oxazepin-11- yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J = 1.7 Hz, 1H), 8.12 (dd, J= 5.0, 1.2 Hz, 1H), 7.73-7.66 (m, 2H), 7.45 (d, J = 1.7 Hz, 1H), 7.40-7.35 (m, 1H), 4.52 (dd, J = 14.1, 3.8 Hz, 1H), 4.13-3.99 (m, 3H), 3.59(t, J = 11.3 Hz, 1H), 3.51-3.38 (m, 4H), 3.19-3.07 (m, 2H), 2.30 (s,3H), 2.19-1.98 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) =540.1, Rt = 1.10 min. 506

(S)-N-(5-(7-ethyl-8- oxo-1,2,4,5,5a,6,7,8- octahydropyrido[2′,3′:6,7][1,4]diazepino [1,2- d][1,4]oxazepin-11- yl)-6-methylpyridin-3-yl)-3- (trifluorometh- yl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ8.87 (d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.28-8.22 (m, 2H), 8.19 (d, J =2.4 Hz, 1H), 7.95-7.89 (m, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.52 (d, J =1.7 Hz, 1H), 4.52 (dd, J = 14.0, 3.8 Hz, 1H), 4.14-4.00 (m, 3H), 3.60(t, J = 11.3 Hz, 1H), 3.53-3.39 (m, 4H), 3.21- 3.07 (m, 2H), 2.51 (s,3H), 2.22- 1.96 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H) =540.1, Rt = 1.01 min. 507

(R)-N-(5-(7-ethyl-8- oxo-1,2,4,5,5a,6,7,8- octahydropyrido[2′,3′:6,7][1,4]diazepino [1,2- d][1,4]oxazepin-11- yl)-6-methylpyridin-3-yl)-3- (trifluorometh- yl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ8.87 (d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.27-8.22 (m, 2H), 8.19 (d, J =2.4 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.52(d, J = 1.7 Hz, 1H), 4.52 (dd, J = 14.0, 3.8 Hz, 1H), 4.14-4.01 (m, 3H),3.60 (t, J = 11.3 Hz, 1H), 3.53-3.39 (m, 4H), 3.21-3.08 (m, 2H), 2.51(s, 3H), 2.19-1.99 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). LCMS (m/z) (M + H)= 540.2, Rt = 1.01 min.

Examples 508 and 509N-(3-(6-(2-hydroxyethoxy)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A mixture of2-((9-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-yl)oxy)ethan-1-ol(1 equiv.),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.1 equiv.), Xphos G2-Pd-Cy (0.05 equiv.), Xphos (0.05 equiv.) andK₃PO₄ (2 equiv., 0.5 M) in dioxane (0.06 M) was stirred at 70° C. blocktemperature for 1 hr. The reaction mixture was poured onto water andextracted with EtOAc. Organic phase was washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by flash chromatography over silica gel (DCM with 0-100% MeOH)to give the desired final product,N-(3-(6-(2-hydroxyethoxy)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(55%). The following two compounds were isolated after chiral separationas outlined in the table below. LCMS (m/z) (M+H)=328.0, Rt=0.91 min.

508

N-(3-((4aR,6R)-6- (2- hydroxyethoxy)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.16-8.08 (m, 1H), 7.91 (d, J = 1.6Hz, 1H), 7.68 (dd, J = 8.2, 2.3 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.34(d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 4.77 (dd, J = 10.3, 6.4Hz, 1H), 3.99 (dd, J = 11.3, 3.5 Hz, 1H), 3.93-3.85 (m, 2H), 3.78-3.65(m, 5H), 3.46-3.40 (m, 1H), 2.84 (td, J = 12.6, 3.6 Hz, 1H), 2.39 (ddt,J = 12.6, 6.3, 3.4 Hz, 1H), 2.27 (s, 3H), 1.78 (dt, J = 12.6, 10.8 Hz,1H). LCMS (m/z) (M + H) = 529.1, Rt = 1.03 min. 509

N-(3-((4aS,6S)-6- (2- hydroxyethoxy)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluorometh- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.12 (d, J = 4.9 Hz, 1H), 7.91 (d, J= 1.3 Hz, 1H), 7.67 (dd, J = 8.2, 2.2 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H),7.33 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.3 Hz, 1H), 4.77 (dd, J = 10.3,6.4 Hz, 1H), 3.99 (dd, J = 11.3, 3.4 Hz, 1H), 3.94-3.84 (m, 2H),3.80-3.64 (m, 5H), 3.43 (t, J = 10.8 Hz, 1H), 2.83 (td, J = 12.6, 3.6Hz, 1H), 2.39 (ddt, J = 12.6, 6.3, 3.3 Hz, 1H), 2.27 (s, 3H), 1.83-1.73(m, 1H). LCMS (m/z) (M + H) = 529.1, Rt = 1.03 min.

The compounds below were prepared using methods similar to thosedescribed for the preparation of examples 508-9 using the appropriateactive reduced ketone and other starting materials:

510

3-fluoro-N-(3- ((4aR,6R)-6-(2- hydroxyethoxy)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.64(d, J = 4.7 Hz, 1H), 7.94 (t, J = 4.8 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H),7.61 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.33 (d, J =8.3 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H), 4.77 (dd, J = 10.3, 6.4 Hz, 1H),4.03- 3.81 (m, 3H), 3.79-3.63 (m, 5H), 3.42 (t, J = 10.8 Hz, 1H),3.37-3.32- 3.23 (m, 1H), 2.94-2.77 (m, 1H), 2.38 (ddd, J = 12.6, 6.4,2.6 Hz, 1H), 2.26 (s, 3H), 1.77 (dt, J = 12.6, 10.8 Hz, 1H). LCMS (m/z)(M + H) = 547.0, Rt = 1.06 min. 511

2-(2-fluoropropan- 2-yl)-N-(3- ((4aR,6R)-6-(2- hydroxyethoxy)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.69 (dt,J = 5.1, 0.8 Hz, 1H), 8.05 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.76 (dd,J = 5.1, 1.7 Hz, 1H), 7.66 (dd, J = 8.2, 2.3 Hz, 1H), 7.62 (d, J = 2.2Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 4.77 (dd, J= 10.3, 6.4 Hz, 1H), 4.05-3.80 (m, 3H), 3.80-3.64 (m, 5H), 3.43 (t, J =10.8 Hz, 1H), 3.38-3.24 (m, 1H), 2.94-2.76 (m, 1H), 2.39 (ddt, J = 12.6,6.4, 3.3 Hz, 1H), 2.27 (s, 3H), 1.84-1.73 (m, 4H), 1.70 (s, 3H). LCMS(m/z) (M + H) = 521.1, Rt = 1.03 min. 512

N-(3-((4aR,6R)-6- (2-hydroxyethoxy)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-6-(trifluorometh- yl)pyridazine-4- carboxamide ¹H NMR (400 MHz,Methanol-d4) δ 9.86 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.90(d, J = 1.7 Hz, 1H), 7.70 (dd, J = 8.2, 2.3 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 1.7 Hz, 1H), 4.78 (dd, J= 10.3, 6.4 Hz, 1H), 4.01 (td, J = 12.6, 11.3, 3.4 Hz, 1H), 3.95- 3.82(m, 2H), 3.78-3.64 (m, 5H), 3.47-3.32 (m, 2H), 2.95-2.77 (m, 1H), 2.39(ddd, J = 12.6, 6.4, 2.6 Hz, 1H), 2.27 (s, 3H), 1.78 (dt, J = 12.6, 10.8Hz, 1H). LCMS (m/z) (M + H) = 530.0, Rt = 1.00 min. 513

2-(1,1- difluoroethyl)-N-(3- ((4aR,6R)-6-(2- hydroxyethoxy)-1,2,4,4a,5,6- hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4-methylphenyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.86-8.74(m, 1H), 8.21-8.12 (m, 1H), 8.01 (s, 1H), 7.98-7.91 (m, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.66- 7.60 (m, 1H), 7.52 (s, 1H), 7.40- 7.30 (m, 1H),4.96-4.88 (m, 1H), 4.03-3.77 (m, 6H), 3.72-3.63 (m, 1H), 3.46-3.35 (m,2H), 2.94 (td, J = 12.2, 3.6 Hz, 1H), 2.57-2.43 (m, 1H), 2.28 (s, 3H),2.01 (t, 3H), 1.83- 1.68 (m, 1H), 1.34-1.29 (m, 1H). LCMS (m/z) (M + H)= 525.1, Rt = 1.01 min. 514

N-(5-((4aR,6R)-6- (2-hydroxyethoxy)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-6- methylpyridin-3-yl)- 3-(trifluorometh- yl)benzamide ¹H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J= 2.5 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.13 (d, J = 2.5Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.93-7.89 (m, 1H), 7.75 (t, J = 7.8Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 4.78 (dd, J = 10.4, 6.3 Hz, 1H),4.03- 3.96 (m, 1H), 3.94-3.86 (m, 2H), 3.78-3.66 (m, 5H), 3.46-3.32 (m,2H), 2.90-2.82 (m, 1H), 2.49 (s, 3H), 2.43-2.36 (m, 1H), 1.79 (dt, J =12.6, 10.7 Hz, 1H). LCMS (m/z) (M + H) = 529.0, Rt = 0.98 min

Intermediates for Examples 515-520.9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carbonitrile

Step 1:

To a solution of9-chloro-5-(ethoxycarbonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1.0 equiv.) in DME (0.15 M) at −15° C. was added4-methylmorpholine (1.2 equiv.) followed by isobutyl chloroformate (1.2equiv.) and stirred for 10 min. NaBH₄(2 equiv.) dissolved in H₂O (1 mL)was added and allowed the reaction mixture to come to ambienttemperature upon which additional NaBH₄ (1.2 equiv.) was added. Thereaction mixture was quenched with acetone and volatiles were evaporatedin vacuo. The reaction mixture was diluted with EtOAc and washed with 1N NaOH. Organic phase was washed with brine, dried over magnesiumsulfate, filtered, and concentrated. The crude product was purified byflash chromatography over silica gel (heptane with 0-100% ethyl acetate)to give the desired product, ethyl9-chloro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate.LCMS (m/z) (M+H)=327.0, Rt=0.90 min.

Step 2:

To a solution of ethyl9-chloro-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1.0 equiv.) in THF (0.11 M) was added triethylamine (12 equiv.)followed by perfluorobutanesulfonyl fluoride (4 equiv.) andtriethylamine trihydrofluoride (4 equiv.). The reaction mixture wasstirred at 60° C. block temperature for 18 hr. The reaction mixture waspoured onto sat. Na₂CO₃ and extracted with EtOAc. Organic phase waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated. The crude product was purified by flash chromatographyover silica gel (heptane with 0 to 100% ethyl acetate) to give theproduct, ethyl9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(100%). LCMS (m/z) (M+H)=329.0, Rt=1.15 min.

Step 3:

To a solution of ethyl9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(1 equiv.) in THF:MeOH (0.1 M, 6 mL:4 mL) was added LiOH (5 equiv.)dissolved in H₂O (2 mL). The reaction mixture was stirred at 70° C.block temperature for 1 hr and concentrated under reduced pressure. Theresidue was acidified with 6 N HCl and extracted with EtOAc, dried overmagnesium sulfate, filtered, and concentrated to give crude product,9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid. LCMS (m/z) (M+H)=301.0, Rt=0.89 min.

Step 4:

To a reaction mixture of9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylicacid (1 equiv.), NH₄Cl (4 equiv.), HATU (1.3 equiv.) in DMF (0.17 M) wasadded DIPEA (4 equiv.) and stirred for 30 min at ambient temperature.The reaction mixture was diluted in EtOAc after concentrated underreduced pressure and washed with Na₂CO_(3.) Organic phase was washedwith brine, dried over magnesium sulfate, filtered, and concentrated togive the crude product,9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxamide.LCMS (m/z) (M+H)=300.0, Rt=0.80 min.

Step 5:

To a solution of9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxamide(1 equiv.) in DCM (0.2 M) was added TEA (6 equiv.) followed by TFAA (4.5equiv.). The reaction mixture was stirred at ambient temperature for 2hrs. The reaction mixture was diluted in EtOAc and washed with NH₄Cl,Na₂CO₃, brine, dried over magnesium sulfate, filtered, and concentrated.The crude product was purified by flash chromatography over silica gel(heptane with 0 to 100% ethyl acetate) to give the product,9-chloro-5-(fluoromethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carbonitrile(65%). LCMS (m/z) (M+H)=282.0, Rt=1.13 and 1.17 min.

The compounds listed in the table below were prepared using theintermediates described above and the appropriate starting materials,followed by chiral purification to provide a single enantiomer anddiastereomer.

515

N-(3-((4aR,5S)-5- cyano-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2- (1,1-difluoroethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.84-8.71 (m, 1H), 8.23-8.11 (m, 1H), 7.94 (dd, J = 3.7, 1.5 Hz, 2H),7.65 (dd, J = 5.5, 2.3 Hz, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.36-7.27 (m,1H), 4.89 (d, J = 9.7 Hz, 1H), 4.77 (d, J = 9.7 Hz, 1H), 4.60 (dd, J =46.4, 9.7 Hz, 1H), 4.21-4.12 (m, 1H), 3.98 (dd, J = 11.7, 3.6 Hz, 1H),3.92-3.82 (m, 1H), 3.79-3.61 (m, 3H), 3.50 (dd, J = 17.0, 2.9 Hz, 1H),3.35 (s, 1H), 3.04 (td, J = 12.2, 3.8 Hz, 1H), 2.26 (s, 3H), 2.03 (t, J= 18.7 Hz, 3H). LCMS (m/z) (M + H) = 522.1, Rt = 1.32 min. 516

N-(3-((4aS,5R)-5- cyano-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2- (1,1-difluoroethyl)iso- nicotinamide 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d,J = 5.0 Hz, 1H), 8.16 (s, 1H), 7.98-7.89 (m, 2H), 7.65 (dd, J = 5.2, 2.2Hz, 2H), 7.40 (d, J = 1.5 Hz, 1H), 7.37-7.28 (m, 1H), 4.89 (d, J = 9.7Hz, 0H), 4.78 (dd, J = 9.5, 5.2 Hz, 1H), 4.60 (dd, J = 46.4, 9.7 Hz,1H), 4.17 (d, J = 9.1 Hz, 1H), 3.98 (dd, J = 11.7, 3.5 Hz, 1H), 3.87 (d,J = 12.3 Hz, 1H), 3.77-3.61 (m, 3H), 3.50 (dd, J = 17.0, 2.9 Hz, 1H),3.35 (s, 1H), 3.04 (td, J = 12.2, 3.8 Hz, 1H), 2.26 (s, 3H), 2.03 (t, J= 18.7 Hz, 3H). LCMS (m/z) (M + H) = 522.1, Rt = 1.32 min. 517

N-(3-((4aS,5S)-5- cyano-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methyphenyl)-2- (1,1-difluoroethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.85-8.74 (m, 1H), 8.17 (s, 1H), 7.96 (d, J = 1.7 Hz, 2H), 7.68 (dd, J =8.2, 2.3 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H),7.34 (d, J = 8.3 Hz, 1H), 4.80-4.73 (m, 1H), 4.66 (q, J = 9.7 Hz, 1H),4.22 (d, J = 11.5 Hz, 1H), 4.04 (dd, J = 11.6, 3.7 Hz, 1H), 3.82 (d, J =12.4 Hz, 1H), 3.74 (td, J = 11.8, 2.8 Hz, 1H), 3.69-3.61 (m, 1H), 3.38(dd, J = 10.7, 3.6 Hz, 1H), 3.26 (s, 2H), 2.97 (td, J = 12.0, 3.9 Hz,1H), 2.28 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H). LCMS (m/z) (M + H) =522.1, Rt = 1.32 min. 518

N-(3-((4aR,5R)-5- cyano-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methyphenyl)-2- (1,1-difluoroethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ8.86-8.74 (m, 1H), 8.22-8.14 (m, 1H), 8.02-7.92 (m, 2H), 7.68 (dd, J =8.2, 2.3 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H),7.34 (d, J = 8.3 Hz, 1H), 4.81-4.74 (m, 1H), 4.66 (q, J = 9.7 Hz, 1H),4.22 (d, J = 11.5 Hz, 1H), 4.04 (dd, J = 11.6, 3.7 Hz, 1H), 3.82 (d, J =12.3 Hz, 1H), 3.74 (td, J = 11.8, 2.8 Hz, 1H), 3.69-3.61 (m, 1H), 3.38(dd, J = 10.7, 3.7 Hz, 1H), 3.26 (s, 2H), 2.97 (td, J = 12.0, 3.8 Hz,1H), 2.28 (s, 3H), 2.03 (t, J = 18.7 Hz, 3H). LCMS (m/z) (M + H) =522.1, Rt = 1.32 min. 519

N-(3-((4aR,5R)-5- cyano-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methylphenyl)-2-(trifluorometh- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.15-8.05 (m, 1H), 7.95 (d, J = 1.6Hz, 1H), 7.71-7.60 (m, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.38-7.29 (m, 1H),4.89 (d, J = 9.7 Hz, 1H), 4.77 (d, J = 9.7 Hz, 1H), 4.61 (dd, J = 46.4,9.7 Hz, 1H), 4.22-4.14 (m, 1H), 3.98 (dd, J = 11.7, 3.6 Hz, 1H),3.91-3.84 (m, 1H), 3.77-3.62 (m, 3H), 3.51 (dd, J = 17.0, 2.9 Hz, 1H),3.35 (d, J = 3.7 Hz, 1H), 3.04 (td, J = 12.2, 3.8 Hz, 1H), 2.27 (s, 3H).LCMS (m/z) (M + H) = 526.1, Rt = 1.27 min. 520

N-(3-((4aR,5S)-5- cyano-5- (fluoromethyl)- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)-4- methyphenyl)-2-(trifluorometh- isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90 (d,J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.95 (d,J = 1.7 Hz, 1H), 7.65 (dd, J = 6.2, 2.3 Hz, 2H), 7.40 (d, J = 1.6 Hz,1H), 7.37- 7.30 (m, 1H), 4.89 (d, J = 9.7 Hz, 1H), 4.77 (d, J = 9.7 Hz,1H), 4.61 (dd, J = 46.4, 9.7 Hz, 1H), 4.21-4.14 (m, 1H), 3.98 (dd, J =11.7, 3.6 Hz, 1H), 3.91- 3.84 (m, 1H), 3.77-3.62 (m, 3H), 3.51 (dd, J =17.0, 2.9 Hz, 1H), 3.35 (d, J = 3.6 Hz, 1H), 3.04 (td, J = 12.2, 3.8 Hz,1H), 2.27 (s, 3H). LCMS (m/z) (M + H) = 526.1, Rt = 1.27 min.

Intermediate for Examples 521-2.4-methyl-3-(6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)aniline

Step 1:

To an ice cold solution of9-chloro-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1.0 equiv.) in THF (0.1 M) was added 3 M MeMgI in ether (7 equiv.) andallowed the reaction mixture to come to ambient temperature and stirredfor 48 hr. The reaction mixture was cooled down and quenched with NH₄C1solution. It was extracted with DCM and organic phase was washed withbrine, dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by flash chromatography over silica gel (heptanewith 50-100% ethyl acetate) to give the product,9-chloro-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(35%). LCMS (m/z) (M+H)=255.0, Rt=0.72 min.

Step 2:

9-chloro-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-ol(1.0 equiv.) and p-toluenesulfonic acid monohydrate (0.5 equiv.) intoluene (0.1 M) was heated to reflux for 1.5 hr. The reaction mixturewas allowed to come to room temperature and quenched with solid K₂CO₃.It was then concentrated to dryness. The crude product was purified byflash chromatography over silica gel (heptane with 0 to 100% ethylacetate) to give the product,9-chloro-6-methyl-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine(58.8%). LCMS (m/z) (M+H)=237.2, Rt=1.19 min.

Step 3:

Using the standard Suzuki coupling method as in Example 1, step 3,isolated product4-methyl-3-(6-methyl-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)aniline(100%). LCMS (m/z) (M+H)=308.1, Rt=0.71 min.

Step 4:

To a nitrogen purged solution of4-methyl-3-(6-methyl-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)aniline(1.0 equiv.) in MeOH (0.11 M) was added 10% Pd—C (0.15 equiv.). Thereaction mixture was purged with hydrogen and hydrogenated with ahydrogen balloon overnight. The reaction mixture was filtered through acelite pad, and the pad was rinsed with MeOH. Filtrate was concentratedto dryness under reduced pressure to giveproduct4-methyl-3-(6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)aniline100% yield. LCMS (m/z) (M+H)=310.1, Rt=1.12 min.

The compounds listed in the table below were prepared using theintermediates above and the appropriate starting materials, followed bychiral purification to provide single enantiomer and diastereomer.

521

N-(4-methyl-3- ((4aR,6S)-6- methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4, 3- a][1,5]naph- thyridin-9- yl)phenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.12 (dd, J = 5.0, 1.2 Hz, 1H), 7.82(d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 4.02 (dd, J= 11.1, 2.3 Hz, 1H), 3.89 (dd, J = 11.1, 2.3 Hz, 1H), 3.75- 3.63 (m,2H), 3.37-3.32 (m, 1H), 3.22- 3.06 (m, 2H), 2.86 (td, J = 12.6, 3.7 Hz,1H), 2.27 (s, 3H), 1.91-1.81 (m, 1H), 1.73 (dt, J = 13.3, 2.5 Hz, 1H),1.37 (d, J = 7.2 Hz, 3H). LCMS (m/z) (M + H) = 483.1, Rt = 1.10 min. 522

N-(4-methyl-3- ((4aR,6R)-6- methyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4, 3- a][1,5]naph- thyridin-9- yl)phenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.90(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.84(d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 4.01 (dd, J= 11.4, 3.6 Hz, 1H), 3.91 (dd, J = 11.4, 3.6 Hz, 1H), 3.76- 3.59 (m,2H), 3.35-3.26 (m, 1H), 3.20- 3.06 (m, 2H), 2.79 (td, J = 11.9, 3.7 Hz,1H), 2.27 (s, 3H), 2.10-2.02 (m, 1H), 1.50 (dt, J = 13.0, 11.7 Hz, 1H),1.43 (d, J = 6.8 Hz, 3H). LCMS (m/z) (M + H) = 483.2, Rt = 1.08 min.

Intermediate for Ex. 525.3-(5-(azidomethyl)-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylaniline

Step 1:

To a reaction mixture of(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methanol91 equiv.), 4-methylbenzenesulfonyl chloride (1.05 equiv.) and DMAP (0.1equiv.) in DCM (0.42 M) was added TEA (1.5 equiv.) and stirred atambient temperature for 2 hr. The reaction mixture was then directlypurified by flash chromatography over silica gel (heptane with 0-100%ethyl acetate) to give the product,(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methyl4-methylbenzenesulfonate (97%) LCMS (m/z) (M+H)=471.9, Rt=1.69 min.

Step 2:

To a solution of(9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-5-yl)methyl4-methylbenzenesulfonate (1 equiv.) in DMF (0.18 M) was added sodiumazide (4 equiv.) and stirred at 105° C. block temperature for 24 hr. Itwas diluted with EtOAc and washed with water, brine, dried over sodiumsulfate, filtered, and concentrated. The crude product was purified byflash chromatography over silica gel (heptane with 0-20% ethyl acetate)to give the product,5-(azidomethyl)-9-bromo-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinoline(92%). LCMS (m/z) (M+H)=342.9, Rt=1.60 min.

Step 3:

Using the standard Suzuki coupling method as in example 116, isolatedproduct3-(5-(azidomethyl)-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylaniline(100%). LCMS (m/z) (M+H)=368.1, Rt=1.10 min.

Example 525:N-(3-((4aS,5R)-5-(aminomethyl)-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(2-fluoropropan-2-yl)isonicotinamide

2-(2-fluoropropan-2-yl)isonicotinic acid (1 equiv.),3-((4aS,5R)-5-(azidomethyl)-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylaniline(1.0 equiv.), EDC.HCl (1.2 equiv.), HOAT (1.2 equiv.) in DMF (0.08 M)were stirred at inert atmosphere for 1 h. It was diluted with EtOAc andwashed with water, brine, dried over sodium sulfate, filtered, andconcentrated. It was further dried under high vac for 14 hrs. Theresidue was then dissolved in THF (2 mL) and triphenylphosphine (polymerbound, 12 equiv.) was added dropwise and the reaction mixture stirred at70° C. block temperature for 2 hr. Water (2 mL) and THF (2 mL) wereadded then the reaction was further heated and stirred at 80° C. blocktemperature for 2 hr. The reaction mixture was allowed to come to roomtemperature and filtered. The filtrate cake was washed with DCM andconcentrated to dryness. It was redissolved in DCM and washed withwater, brine, dried over magnesium sulfate, filtered, and concentrated.The crude product was purified by reverse phase ISCO flashchromatography (no modifier) to give the desired product,N-(3-((4aS,5R)-5-(aminomethyl)-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(2-fluoropropan-2-yl)isonicotinamide(8.7%). 1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J=5.1 Hz, 1H), 8.05 (s,1H), 7.75 (dd, J=5.1, 1.7 Hz, 1H), 7.63-7.54 (m, 2H), 7.26 (d, J=8.0 Hz,1H), 7.14 (d, J=7.6 Hz, 1H), 6.85-6.72 (m, 2H), 4.03 (dd, J=11.4, 3.0Hz, 1H), 3.95-3.85 (m, 1H), 3.79-3.56 (m, 3H), 3.25-3.14 (m, 1H),3.12-2.98 (m, 2H), 2.96-2.85 (m, 1H), 2.83-2.70 (m, 1H), 2.24 (s, 3H),1.75 (s, 3H), 1.70 (s, 3H). LCMS (m/z) (M+H)=507.1, Rt=1.11 min.

Example 526:N-(5-((4aS,5R)-5-(aminomethyl)-5-fluoro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide

This compound was synthesized using the same method as Example 525 usingappropriate starting material in the Suzuki-cross coupling reaction. ¹HNMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.5 Hz, 1H), 8.29 (s, 1H), 8.23(d, J=7.9 Hz, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.74(t, J=7.8 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 6.85 (d, J=1.3 Hz, 1H), 6.81(dd, J=7.5, 1.5 Hz, 1H), 4.04 (dd, J=11.4, 3.0 Hz, 1H), 3.91 (dd,J=11.2, 3.3 Hz, 1H), 3.77-3.60 (m, 3H), 3.38 (ddt, J=20.0, 3.3, 1.7 Hz,1H), 3.25-3.15 (m, 1H), 3.11-2.69 (m, 4H),2.47 (s, 3H). LCMS (m/z)(M+H)=515.2, Rt=1.34 min.

Intermediate for Example 527.9-bromo-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-amine

Step 1:

To an ice cold solution of9-bromo-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1.0 equiv.) in THF (0.12 M) was added NaH (3 equiv.) and stirred for 30min. Iodomethane (3 equiv.) was then added and allowed the reactionmixture to come to ambient temperature. It was stirred for 45 min,poured onto saturated aqueous NH₄Cl and extracted with EtOAc. Theorganic phase was washed with sat. NaHCO₃. The combined aqueous layerwas back extracted with EtOAc. The combined organic phase was washedwith brine, dried over magnesium sulfate, filtered, and concentrated.The crude product was purified by flash chromatography over silica gel(hept with 0-100% ethyl acetate) to give9-bromo-5,5-dimethyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-onein 39% yield. LCMS (m/z) (M+H)=313.1, Rt=1.00 min.

Step 2:

A mixture of9-bromo-5,5-dimethyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6(4H)-one(1 equiv.), hydroxylamine hydrochloride (6 equiv.) and sodium acetate (6equiv.) in EtOH (0.046 M) was heated to reflux for 4.5 hr. The reactionmixture was concentrated to dryness and re-dissolved in EtOAc. It waswashed with water, brine, dried over sodium sulfate, filtered, andconcentrated. To this was added acetic acid (55 equiv.) and Zn dust (8equiv.). The reaction mixture was filtered through a pad of celite afterstirring for 1 hr. The filter pad was rinsed with EtOH and concentrated.To this solid residue was added NH₄OH (1 mL) and DCM (10 mL) and stirredfor 10 min. Organic layer was separated. Aqueous layer was extractedwith DCM twice. The combined organic phase was washed with brine, driedover sodium sulfate, filtered, and concentrated to dryness to give9-bromo-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-6-amine(100%). LCMS (m/z) (M+H)=313.9, Rt=0.78 min.

527

N-(3-((4aR,6R)- 6-amino-5,5- dimethyl- 1,2,4,4a,5,6- hexahydro-[1,4]oxazino[4,3- a][1,5]naph- thyridin-9-yl)-4- methylphenyl)-2-(trifluorometh- yl)isonicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91(d, J = 5.0 Hz, 1H), 8.28 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 8.06(d, J = 1.6 Hz, 1H), 7.74 (t, J = 2.5 Hz, 1H), 7.58 (dt, J = 8.2, 2.2Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.09 (s,1H), 4.02 (dd, J = 11.3, 3.2 Hz, 1H), 3.98-3.89 (m, 2H), 3.66 (td, J =11.9, 2.7 Hz, 1H), 3.58 (t, J = 11.0 Hz, 1H), 3.19 (dd, J = 10.6, 3.3Hz, 1H), 3.13-3.04 (m, 1H), 2.27 (s, 3H), 1.19 (s, 3H), 1.14 (s, 3H).LCMS (m/z) (M + H) = 512.2, Rt = 1.07 min.

Intermediate for Example 528.10-bromo-6,6-difluoro-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-ol

Step 1:

To a solution10-bromo-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-one(0.1 equiv.) in THF (0.16 M) was added NaH (6 equiv.) and stirred for 20min. at an ambient temperature. To this was addedN-fluorobenzenesulfonimide (4 equiv.) and stirred for 2 hr. The reactionmixture was quenched with sat. NH₄Cl solution and extracted with EtoAc.Organic layer was washed with sat. NaHCO₃ solution, brine, dried oversodium sulfate, filtered and concentrated. It was purified by flashchromatography over silica gel (Heptane with 0-50% EtOAc) to give10-bromo-6,6-difluoro-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-onein 5.8% yield. LCMS (m/z) (M+H)=334.1, Rt=1.42 min.

Step 2:

To a cooled mixture of10-bromo-6,6-difluoro-1,2,4,5,5a,6-hexahydro-7H-[1,4]oxazepino[4,5-a]quinolin-7-one(1 equiv.) at −20° C. in THF (0.08 M), was d added L-selectride (4equiv.), and the reaction mixture was allowed to come to ambienttemperature over 1 hr. The reaction mixture was quenched with dropwiseaddition of H₂O. The reaction mixture was concentrated under reducedpressure, diluted with EtOAc, washed with sat. NH₄Cl solution. Theorganic extracts were dried over magnesium sulfate, filtered, andconcentrated to give10-bromo-6,6-difluoro-1,2,5,5a,6,7-hexahydro-4H-[1,4]oxazepino[4,5-a]quinolin-7-olin 100% yield. LCMS (m/z) (M+H)=336.3, Rt=1.26 min.

528

N-(3-((5aS,7S)- 6,6-difluoro-7- hydroxy- 1,2,5,5a,6,7- hexahydro-4H-[1,4]oxazepino[4,5- a]quinolin-10-yl)- 4-methyl)phenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.63(dd, J = 8.2, 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.2Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.72 (dd, J = 7.7, 1.4 Hz, 1H), 6.64(d, J = 1.1 Hz, 1H), 4.81-4.74 (m, 1H), 4.01-3.86 (m, 3H), 3.86-3.71 (m,3H), 3.50- 3.39 (m, 1H), 2.66-2.53 (m, 1H), 2.26 (s, 3H), 2.17-2.06 (m,1H). LCMS (m/z) (M + H) = 534.1, Rt = 1.52 min.

Example 529:N-(3-((4aR,6R)-6-acetamido-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

To a solution ofN-(3-((4aR,6R)-6-amino-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(1.0 equiv.) in pyridine (0.26 M) was added acetic anhydride (50 equiv.)and stirred for 30 min at ambient temperature. It was diluted with EtOAcand washed with sat. NH₄Cl solution, brine, dried over sodium sulfate,filtered, and concentrated. The crude product was purified by flashchromatography over silica gel (DCM with 0-50% MeOH) to give the desiredproductN-(3-((4aR,6R)-6-acetamido-5,5-dimethyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(35.7%). 1H NMR (400 MHz, Methanol-d4) δ 8.90 (d, J=5.0 Hz, 1H), 8.29(s, 1H), 8.11 (dd, J=5.0, 1.2 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.69-7.60(m, 2H), 7.36-7.31 (m, 1H), 7.28 (d, J=1.7 Hz, 1H), 5.13 (s, 1H), 4.07(dd, J=11.4, 3.1 Hz, 1H), 3.98 (dd, J=11.5, 3.5 Hz, 1H), 3.78 (d, J=12.2Hz, 1H), 3.66 (td, J=11.8, 2.9 Hz, 1H), 3.55 (t, J=11.0 Hz, 1H), 3.22(dd, J=10.7, 3.4 Hz, 1H), 2.93 (td, J=12.0, 3.8 Hz, 1H), 2.26 (s, 3H),1.93 (s, 3H), 1.03 (s, 3H), 0.94 (s, 3H). LCMS (m/z) (M+H)=554.2,Rt=1.06 min.

Intermediate for Examples 530-531.1-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)-N-methylmethanamine

Step 1:

To an ice cold solution ethyl9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxylate(0.1 equiv.) in THF (0.2 M) was drop-wise added lithium aluminum hydridein THF (1.1 equiv., 1M) and stirred for 10 min. To this was added sodiumsulfate decahydrate (1 equiv.) and allowed the reaction mixture to cometo ambient temperature. The reaction mixture was diluted with EtOAc andfiltered through a celite pad. The combined filtrate after washing thepad were concentrated to give(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanolin 98% yield. LCMS (m/z) (M+H)=255.1, Rt=0.66 min.

Step 2:

To a vial containing mixture of(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methanol(1 equiv.), 4-methylbenzenesulfonyl chloride (1.05 equiv.), DMAP (0.1equiv.) and DCM (0.2 M) was added TEA (1.4 equiv.) and stirred for 2 hr.The reaction mixture was directly purified via flash chromatography oversilica gel (Heptane with 0-100% EtOAc) to give(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methyl4-methylbenzenesulfonate in 94% yield. LCMS (m/z) (M+H)=409.4, Rt=1.27min.

Step 3:

To a solution of(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)methyl4-methylbenzenesulfonate (1 equiv.) in DMSO (0.6 M) was added methylamine in THF (10 equiv., 2 M) and stirred at 60° C. for 48 hr. It wasallowed to come to ambient temperature. It was diluted with EtOAc,washed with sat. NaHCO₃ solution, water, brine, dried over sodiumsulfate, filtered, and concentrated. This crude material was purifiedvia chiral separation to give two chirally pure compounds,1-(9-chloro-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-5-yl)-N-methylmethanamine.LCMS (m/z) (M+H)=268.1, Rt=0.61 min.

The compounds listed in the following table were prepared using theabove intermediate and the appropriate starting materials:

530

N-(4-methyl-3- ((4aR,5S)-5- ((methylamino)meth- yl)-1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)phenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.89(d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 7.79(d, J = 1.7 Hz, 1H), 7.69-7.59 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.19(d, J = 1.6 Hz, 1H), 4.01 (dd, J = 11.2, 3.1 Hz, 1H), 3.94 (dd, J =10.9, 3.2 Hz, 1H), 3.74-3.62 (m, 2H), 3.42 (t, J = 10.9 Hz, 1H), 3.07-2.95 (m, 3H), 2.77 (dd, J = 16.4, 8.9 Hz, 1H), 2.63 (dd, J = 12.0, 5.5Hz, 1H), 2.52 (dd, J = 12.0, 7.8 Hz, 1H), 2.41 (s, 3H), 2.26 (s, 3H),2.13- 2.04 (m, 1H). LCMS (m/z) (M + H) = 512.2, Rt = 0.88 min. 531

N-(4-methyl-3- ((4aS,5R)-5- ((methylamino)meth- yl)-1,2,4,4a,5,6-hexahydro- [1,4]oxazino[4,3- a][1,5]naphthyridin- 9-yl)phenyl)-2-(trifluoromethyl)iso- nicotinamide ¹H NMR (400 MHz, Methanol-d4) δ 8.91(d, J = 5.0 Hz, 1H), 8.28 (s, 1H), 8.11 (dd, J = 5.0, 1.2 Hz, 1H), 8.03(d, J = 1.5 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H),7.61 (dd, J = 8.3, 2.3 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.09-3.93 (m,3H), 3.66 (td, J = 11.9, 2.7 Hz, 1H), 3.49 (t, J = 10.8 Hz, 1H), 3.42-3.32 (m, 2H), 3.28-3.19 (m, 2H), 3.13-3.02 (m, 2H), 2.80 (s, 3H),2.51-2.38 (m, 1H), 2.30 (s, 3H). LCMS (m/z) (M + H) = 512.2, Rt = 0.88min.

2-(1,1-Difluoroethyl)-N-(3-((6S,6aR)-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(Ex. 532),2-(1,1-difluoroethyl)-N-(3-((6R,6aR)-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(Ex. 533), and2-(1,1-difluoroethyl)-N-(3-((6S,6aS)-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(Ex. 534)

A vial was charged with2-chloro-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazine(1 equiv),2-(1,1-difluoroethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(1.2 equiv), XPhos 2nd Gen Precatalyst (5 mol %), potassium phosphate (3equiv), and a 4:1 mixture of 1,4-dioxane and water (0.1 M). The vial wassealed and heated to 120° C. for 1 h in a Biotage Initiator microwavereactor. The mixture was extracted with EtOAc (3×), and the combinedorganic extracts were concentrated. The residue was purified bychromatography on silica gel (24-g Redi-Sep Gold column, 75-100%EtOAc/heptane) to give2-(1,1-difluoroethyl)-N-(3-(6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(78% yield) as a light-yellow foam as a mixture of stereoisomers. Themixture was purified by chiral SFC, and the resulting pure stereoisomerswere lyophylized from acetonitrile/water to afford white solids. Thefirst eluting peak afforded2-(1,1-Difluoroethyl)-N-(3-((6S,6aR)-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(Ex. 532): ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1H) 8.88 (d, J=5.01Hz, 1H) 8.19 (s, 1H) 8.04 (d, J=4.89 Hz, 1H) 7.76-7.81 (m, 2H) 7.30-7.38(m, 1H) 7.10 (s, 1H) 4.34-4.39 (m, 1H) 3.89-4.01 (m, 2H) 3.84 (dd,J=11.49, 3.06 Hz, 1H) 3.64 (dt, J=10.82, 3.03 Hz, 1H) 3.48 (td, J=11.77,2.26 Hz, 1H) 3.33-3.40 (m, 1H) 3.06-3.27 (m, 1H) 2.28 (s, 3H) 2.05 (t,J=19.13 Hz, 3H) 1.48-1.71 (m, 2H) 0.97-1.14 (m, 3H). LMCS (m/z)(M+H)=496.0, Rt=1.21 min. The second peak afforded2-(1,1-difluoroethyl)-N-(3-((6R,6aR)-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(Ex. 533): ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H) 8.88 (d, J=5.01Hz, 1H) 8.19 (s, 1H) 8.04 (d, J=4.65 Hz, 1H) 7.78 (d, J=6.43 Hz, 2H)7.77 (s, 1H) 7.32 (d, J=9.05 Hz, 1H) 7.02 (s, 1H) 4.11 (td, J=7.73, 2.87Hz, 1H) 3.93-4.05 (m, 2H) 3.81 (br d, J=11.37 Hz, 1H) 3.34-3.59 (m, 1H)3.21-3.29 (m, 2H) 2.93 (td, J=12.38, 3.73 Hz, 1H) 2.27 (s, 3H) 2.05 (t,J=19.13 Hz, 3H) 1.73-1.89 (m, 1H) 1.63 (dt, J=14.70, 7.50 Hz, 1H)1.01-1.15 (m, 3H). LMCS (m/z) (M+H)=496.0, Rt=1.21 min. The thirdeluting peak afforded2-(1,1-difluoroethyl)-N-(3S,6aS)-6-ethyl-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyridazino[3,4-b][1,4]oxazin-2-yl)-4-methylphenyl)isonicotinamide(Ex. 534): ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H) 8.88 (d, J=5.01Hz, 1H) 8.19 (s, 1H) 8.04 (d, J=4.65 Hz, 1H) 7.78 (d, J=6.43 Hz, 2H)7.77 (s, 1H) 7.32 (d, J=9.05 Hz, 1H) 7.02 (s, 1H) 4.11 (td, J=7.73, 2.87Hz, 1H) 3.93-4.05 (m, 2H) 3.81 (br d, J=11.37 Hz, 1H) 3.34-3.59 (m, 1H)3.21-3.29 (m, 2H) 2.93 (td, J=12.38, 3.73 Hz, 1H) 2.27 (s, 3H) 2.05 (t,J=19.13 Hz, 3H) 1.73-1.89 (m, 1H) 1.63 (dt, J=14.70, 7.50 Hz, 1H)1.01-1.15 (m, 3H). LMCS (m/z) (M+H)=496.0, Rt=1.21 min.

Biological Assays

The activity of a compound according to the present invention can beassessed by well-known in vitro & in vivo methods. Raf inhibition dataprovided herein was obtained using the following procedures.

In Vitro Raf Activity Determination: The RAF enzymes and thecatalytically inactive MEK1 protein substrate were all made in-houseusing conventional methods. CRAF cDNA was subcloned as full lengthprotein, with Y340E and Y341E activating mutations, into a baculovirusexpression vector for Sf9 insect cell expression. h14-3-3 zeta cDNA wassubcloned into a baculovirus expression vector for SF9 insect cellexpression. Sf9 cells co-expressing both proteins were lysed andsubjected to immobilized nickel chromatography and eluted withImidazole. A second column (StrepII binding column) was used and elutedwith desthiobiotin. Protein Tags were removed using Prescission enzymeand the protein was further purified using a flowthrough step to removetags.

C-Raf TR refers to a truncated C-Raf protein, a Δ1-324 deletion mutant.C-Raf FL refers to the full-length C-Raf protein.

Full length MEK1 with an inactivating K97R ATP binding site mutation isutilized as a RAF substrate. The MEK1 cDNA was subcloned with anN-terminal (his)₆ tag into a vector for E. Coli expression. The MEK1substrate was purified from E. Coli lysate by nickel affinitychromatography followed by anion exchange. The final MEK1 preparationwas biotinylated (Pierce EZ-Link Sulfo-NHS-LC-Biotin) and concentrated.

Assay Materials: Assay buffer is 50 mM Tris, pH 7.5, 15 mM MgCl₂, 0.01%Bovine Serum Albumin (BSA) and 1 mM dithiothreitol (DTT); Stop buffer is60 mM ethylenediaminetetraacetic acid (EDTA) and 0.01% Tween® 20; b-Raf(V600E), active; biotinylated Mek, kinase dead; Alpha Screen detectionkit (available from PerkinElmer™, #6760617R); Anti phospho-MEK1/2(available from Cell Signaling Technology, Inc. #9121); 384 well lowvolume assay plates (White Greiner® plates).

Assay conditions: b-Raf (V600E) approximately 4 pM; c-Raf approximately4 nM; biotinylated Mek, kinase dead approximately 10 nM; ATP 10 μM forBRAF (V600E) and 1 μM for CRAF; Pre-incubation time with compounds 60minutes at room temperature; Reaction time 1 or 3 hours at roomtemperature.

Assay protocol: Raf and biotinylated Mek (kinase dead) were combined at2× final concentrations in assay buffer (50 mM Tris, pH 7.5, 15 mMMgCl₂, 0.01% BSA and 1 mM DTT) and dispensed 5 ml per well in assayplates (Greiner white 384 well assay plates #781207) containing 0.25 mlof 40× of a Raf kinase inhibitor test compound diluted in 100% DMSO. Theplate was incubated for 60 minutes at room temperature. The Raf kinaseactivity reaction was started by the addition of 5 mL per well of 2×ATPdiluted in assay buffer. After 3 hours (b-Raf(V600E)) or 1 hour (c-Raf).The reactions were stopped and the phosphorylated product was measuredusing a rabbit anti-p-MEK (Cell Signaling, #9121) antibody and the AlphaScreen IgG (ProteinA) detection Kit (PerkinElmer #6760617R), by theaddition of 10 mL to the well of a mixture of the antibody (1:2000dilution) and detection beads (1:2000 dilution of both beads) inStop/bead buffer (25 mM EDTA, 50 mM Tris, pH 7.5, 0.01% Tween20). Theadditions were carried out under dark conditions to protect thedetection beads from light. A lid was placed on top of the plate andincubated for 1 hour at room temperature, after which the luminescencewas read on a PerkinElmer Envision instrument. The concentration of eachcompound for 50% inhibition (IC₅₀) was calculated by non-linearregression using XL Fit data analysis software.

Using the assays described above, compounds of the invention exhibitinhibitory efficacy for C-Raf. The Bioactivity Table below summarizesIC50 data for compounds of the Examples.

BIOACTIVITY TABLE Example C-RAF IC50 μM 1 0.000045 2 0.000136 3 0.0000314 0.0000062 5 0.000036 6 0.000076 7 0.000033 8 0.00019 9 0.000051 100.000036 11 0.0000098 12 0.0000072 13 0.0000055 14 0.000034 15 0.00008416 0.000055 17 0.000046 18 NA 19 0.000019 20 0.000025 21 0.0000012 220.00023 23 0.000046 24 0.000049 25 0.00052 26 0.000014 27 0.000017 280.000059 29 0.00017 30 0.00018 31 0.000033 32 0.000023 33 0.0000082 340.0000087 35 0.000018 36 0.000013 37 0.0000081 38 0.000030 39 0.000002340 0.000066 41 0.0000099 42 0.000015 43 0.0000082 44 0.000037 45 0.0001746 0.000014 47 0.000073 48 0.000049 49 0.000021 50 0.000013 51 0.00003652 0.00016 53 0.0000062 54 0.000013 55 0.000022 56 0.000071 57 0.00001158 0.000010 59 0.0000089 60 0.000019 61 0.000033 62 0.000015 63 0.00002064 0.000013 65 0.0000060 66 0.00011 67 0.00013 68 0.00034 69 0.000028 700.000032 71 0.000027 72 0.000014 73 0.00020 74 0.00028 75 0.00048 760.000 77 78 0.000020 79 0.000038 80 0.00042 81 0.000081 82 0.00017 830.00085 84 0.0010 85 0.000070 86 0.000027 87 0.000022 88 0.000032 890.000036 90 0.000023 91 0.000076 92 0.00061 93 0.000025 94 0.000019 950.000030 96 0.000053 97 0.000014 98 0.00056 99 0.000038 100 0.000037 1010.000026 102 <0.0000017 103 0.000013 104 0.000044 105 0.000045 1060.000012 107 0.000019 108 0.000013 109 0.0000057 110 0.0000020 1110.0000054 112 <0.0000017 113 0.0000084 114 0.000070 115 0.000011 116<0.0000017 117 0.0000047 118 0.0000046 119 0.000010 120 0.000011 1210.0000095 122 0.0000050 123 0.0000052 124 0.0000094 125 0.000034 1260.000016 127 0.000048 128 0.000023 129 0.00018 130 0.00037 131 0.000060132 0.00014 133 0.000011 134 0.000016 135 0.000019 136 0.000018 1370.00024 138 0.00059 139 0.000057 140 0.0000085 141 0.0000042 1420.000021 143 0.0000088 144 0.0000023 145 0.000017 146 0.000012 1470.0000026 148 0.000046 149 0.000013 150 0.000079 151 0.000014 1520.000011 153 0.0000048 154 0.000063 155 0.00036 156 0.000048 157 0.00016158 0.000010 159 0.0000068 160 0.000027 161 0.00008 162 0.000093 1630.000020 164 0.00043 165 0.00062 166 0.000011 167 0.000077 168 0.00077169 0.000032 170 0.000025 171 0.000019 172 0.000034 173 0.000012 2340.0013 235 0.0009 236 0.0003 237 0.0013 238 0.0027 239 0.0047 240 0.0106241 0.0095 242 0.0003 243 0.0006 244 0.0001 245 0.0002 246 0.0002 2470.0003 248 0.0005 249 0.0001 250 0.0003 251 0.0002 252 0.0001 253 0.0032254 0.0002 255 0.0008 256 0.0001 257 0.0000 258 0.0000 259 0.0006 2600.0001 261 0.0002 262 0.0007 263 0.0003 265 0.0001 266 0.0003 267 0.0000268 0.0003 269 0.0003 270 0.0002 271 0.0002 272 0.0005 273 0.0002 2740.0005 275 0.0008 276 0.0005 277 0.0001 278 0.0003 279 0.0004 280 0.0005281 0.0002 283 0.0002 284 0.0000 285 0.0001 286 0.0000 287 0.0002 2880.0009 289 0.0009 290 0.0010 291 0.0001 292 0.0001 293 0.0001 294 0.0001295 0.0001 296 0.0018 297 0.0002 298 0.0003 299 0.0001 300 0.0002 3010.0000 302 0.0001 303 0.0001 304 0.0005 305 0.0003 306 0.0001 307 0.0001308 0.0007 309 0.0003 310 0.0001 311 0.0001 312 0.0001 313 0.0005 3140.0006 315 0.0017 316 0.0008 317 0.0017 318 0.0014 319 0.0022 320 0.0008322 0.0003 323 0.0002 324 0.0008 325 0.0001 326 0.0005 327 0.0003 3280.0001 329 0.0002 330 0.0031 331 0.0066 332 0.0021 333 0.0000 334 0.0004335 0.0001 336 0.0002 337 0.0003 338 0.0005 339 0.0005 340 0.0013 3410.0006 342 0.0001 343 0.0002 344 0.0001 345 0.0008 346 0.0001 347 0.0003348 0.0007 349 0.0030 351 0.0011 352 0.0001 353 0.0000 354 0.0003 3550.0012 356 0.0001 357 0.0000 358 0.0001 359 0.0003 360 0.0000 361 0.0009362 0.0002 363 0.0001 364 0.0008 365 0.0002 366 0.0000 367 0.0010 3680.0001 369 0.0003 370 0.0001 371 0.0002 372 0.0003 373 0.0004 374 0.0002375 0.0004 376 0.0005 377 0.0009 378 0.0002 379 0.0011 380 0.0004 3810.0003 382 0.0002 383 0.0010 384 0.0002 385 0.0006 386 0.0003 387 0.0003388 0.0004 389 0.0005 390 0.0017 391 0.0068 392 0.0034 393 0.0001 3940.0003 395 0.0002 396 0.0002 397 0.0000 398 0.0000 399 0.0003 400 0.0001401 0.0003 403 0.0001 404 0.0000 405 0.0002 406 0.0004 407 0.0001 4080.0007 409 0.0004 410 0.0005 411 0.0002 412 0.0004 413 0.0002 414 0.0005415 0.0008 416 0.0004 417 0.0005 418 0.0021 419 0.0005 420 0.0006 4210.0008 422 0.0010 423 0.0007 424 0.0002 425 0.0004 426 0.0004 427 0.0006428 0.0001 429 0.0008 430 0.0006 431 0.0044 432 0.0007 433 0.0001 4340.0013 436 0.0003 437 0.0006 438 0.0008 439 0.0001 440 0.0003 441 0.0000442 0.0007 443 0.0006 444 0.0004 445 0.0007 446 0.0007 447 0.0005 4480.0002 449 0.0007 450 0.0002 451 0.0006 452 0.0005 453 0.0007 454 0.0008455 0.0013 456 0.0007 457 0.0004 458 0.0007 459 0.0004 460 0.0002 4610.0022 462 0.0007 463 0.0021 464 0.0007 465 0.0020 466 0.0009 467 0.0019468 0.0080 469 0.0018 470 0.0022 471 0.0012 472 0.0020 473 0.0015 4740.0055 475 0.0004 476 0.0002 477 0.0001 478 0.0002 479 0.0004 480 0.0002481 0.0011 482 0.0003 483 0.0010 484 0.0041 485 0.0003 486 0.0016 4870.0007 488 0.0003 489 0.0004 490 0.0005 491 0.0000 492 0.0002 493 0.0001494 0.0001 495 0.0001 496 0.0007 497 0.0014 498 0.0006 499 0.0004 5000.0001 501 0.0002 502 0.0002 503 0.0001 504 0.0154 505 0.0036 506 0.0803507 0.0269 508 0.0002 509 0.0002 510 0.0001 511 0.0002 512 0.0004 5130.0001 514 0.0004 515 0.0001 516 0.0001 517 0.0001 518 0.0001 519 0.0000520 0.0001 521 0.0005 522 0.0001 525 0.0015 526 0.0026 527 0.0009 5280.0007 529 0.0023 530 0.0004 531 0.0002 532 0.0002 533 0.0001 534 0.0001

We claim:
 1. A compound of formula (A):

in which: R′ is selected from the group consisting of H and methyl; R₁is C₁₋₃alkyl substituted by CN or by one or more halogens; R₂ isselected from the group consisting of:

wherein Z₁ is CR₃R₄, —O—, a bond, or CR₇; provided that when Z₁ is CR₇,Z₁ is attached to the carbon atom bonded to R₉ by a double bond and R₉is absent; Z₂ is CR₅R₆, O, —C(O)NR₈—[Y₆], —NR₈C(O)—[Y₆], or—(CR₇)₀₋₁—C(O)—[Y₆], where [Y₆] indicates which atom of Z₂ is attachedto the ring containing Y₆; provided Z₁ and Z₂ are not bothsimultaneously O; Z₃ is a carbon atom bonded to Y₆ by an aromatic bond,or Z₃ is a nitrogen atom bonded to Y₆ by a single bond; R₃ is selectedfrom the group consisting of hydrogen, C₁₋₃alkyl, halo,C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl andhydroxy-substituted-C₁₋₃alkyl; R₄ is selected from the group consistingof hydrogen, amino, C₁₋₃alkyl, cyano, hydroxy-ethyl and halo; or R₃ andR₄ together with the carbon atom to which R₃ and R₄ are attached form a4 member saturated cyclic ring containing an oxygen molecule; R₅ isselected from the group consisting of hydrogen, halo, amino,C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, hydroxy and C₁₋₃alkoxy; R₆is selected from the group consisting of hydrogen, C₁₋₃alkyl, halo,halo-substituted-C₁₋₃alkyl; or R₄ and R₆ together with the carbon atomto which R₄ and R₆ are attached form 5-6 member unsaturated ringcontaining up to 2 heteroatoms selected from O, S and N; wherein saidring is optionally substituted with C₁₋₂alkyl; R₇ is selected from thegroup consisting of hydrogen, hydroxy-carbonyl and C₁₋₃alkoxy-carbonyl;R₈ is selected from the group consisting of hydrogen,C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, C₁₋₃alkoxy andhydroxy-substituted-C₁₋₄alkoxy, hydroxy-substituted-C₁₋₃alkyl, andC₁₋₃alkyl; R₉ is independently selected at each occurrence from thegroup consisting of hydrogen, fluorine, and methyl; each R₁₀ representsan optional substituent selected from the group consisting of C₁₋₃ alkyland C₁₋₃ alkoxy, or two R₁₀ on non-adjacent ring atoms can be takentogether to form a bond or a (CH₂)₁₋₂ bridge linking the twonon-adjacent ring atoms to form a fused or bridged ring; Y₀ is selectedfrom the group consisting of N, CH and CF; Y₁ is selected from the groupconsisting of N and CH; Y₂ is selected from the group consisting of N,CH, CF, CCl, C—NH₂, and C—C(R₉)₂NH₂; Y₃ is selected from the groupconsisting of N and CH; Y₄ is selected from the group consisting of Nand CH; Y₅ is selected from the group consisting of N and CH; and Y₆ isselected from the group consisting of N and CH when Z₃ is carbon, and Y₆is C(═O) when Z₃ is nitrogen; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein R′ is methyl.
 3. Thecompound of claim 1, wherein Y₄ is CH.
 4. The compound of claim 1,wherein Y₄ is N.
 5. The compound of claim 1, wherein Y₀ is CH.
 6. Thecompound of claim 1, wherein Y₁ is N.
 7. The compound of claim 1,wherein Y₂ is CH.
 8. The compound of claim 1, wherein Y₃ is CH.
 9. Thecompound of claim 1, wherein Y₅ is CH.
 10. The compound of claim 1,wherein Y₆ is CH.
 11. The compound of claim 1, wherein R₉ is H.
 12. Thecompound of claim 1, wherein Z₁ is CH₂ or a bond.
 13. The compound ofclaim 1, wherein R₂ is selected from the group consisting of:

wherein Y₆ is selected from the group consisting of N and CH; Z₁ isCR₃R₄ or a bond; and Z₂ is CR₅R₆, —C(O)NR₈—[Y₆] or —NR₈C(O)—[Y₆], where[Y₆] indicates which atom of Z₂ is attached to the ring containing Y₆.14. The compound of claim 1, which is of the formula (I):

in which: R′ is selected from the group consisting of H and methyl; R₁is halo-substituted C₁₋₃alkyl; R₂ is selected from the group consistingof:

R₃ is selected from the group consisting of hydrogen, C₁₋₃alkyl, halo,C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl andhydroxy-substituted-C₁₋₃alkyl; R₄ is selected from the group consistingof hydrogen, amino, C₁₋₃alkyl, cyano, hydroxy-ethyl and halo; or R₃ andR₄ together with the carbon atom to which R₃ and R₄ are attached form a4 member saturated cyclic ring containing an oxygen molecule; R₅ isselected from the group consisting of hydrogen, halo, amino,C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, hydroxy and C₁₋₃alkoxy; R₆is selected from the group consisting of hydrogen, C₁₋₃alkyl, halo,halo-substituted-C₁₋₃alkyl; or R₄ and R₆ together with the carbon atomto which R₄ and R₆ are attached form 5-6 member unsaturated ringcontaining up to 2 heteroatoms selected from O, S and N; wherein saidring is optionally substituted with C₁₋₂alkyl; each R₇ is selected fromthe group consisting of hydrogen, hydroxy-carbonyl andC₁₋₃alkoxy-carbonyl; R₈ is selected from the group consisting ofhydrogen, C₁₋₃alkyl-amino-carbonyl, C₁₋₃alkyl-carbonyl, C₁₋₃alkoxy andhydroxy-substituted-C₁₋₄alkoxy and C₁₋₃alkyl; R₉ is selected from thegroup consisting of hydrogen and methyl; Y₁ is selected from the groupconsisting of N and CH; Y₂ is selected from the group consisting of Nand CH; Y₃ is selected from the group consisting of N and CH; Y₄ isselected from the group consisting of N and CH; Y₅ is selected from thegroup consisting of N and CH; and Y₆ is selected from the groupconsisting of N and CH; or the pharmaceutically acceptable salt thereof.15. The compound of claim 1 which is a compound of formula (Ia):

in which: R₁ is halo-substituted C₁₋₃alkyl; R₈ is selected from thegroup consisting of hydrogen and C₁₋₃alkyl; R₉ is selected from thegroup consisting of hydrogen and methyl; Y₁ is selected from the groupconsisting of N and CH; Y₂ is CH; Y₃ is CH; Y₄ is selected from thegroup consisting of N and CH; Y₅ is selected from the group consistingof N and CH; and Y₆ is selected from the group consisting of N and CH;or the pharmaceutically acceptable salt thereof.
 16. The compound ofclaim 1, in which: R₁ is selected from the group consisting oftrifluoromethyl, 2-fluoropropan-2-yl, 2-cyanopropan-2-yl and1,1-difluoroethyl; R₈ is selected from the group consisting of hydrogenand ethyl; Y₁ is selected from the group consisting of N and CH; Y₄ isselected from the group consisting of N and CH; Y₅ is selected from thegroup consisting of N and CH; and Y₆ is selected from the groupconsisting of N and CH; or the pharmaceutically acceptable salt thereof.17. The compound of claim 1, which is a compound of formula (Ib):

in which: R₁ is halo-substituted C₁₋₃alkyl; R₃ is selected from thegroup consisting of hydrogen, C₁₋₃alkyl, halo, C₁₋₃alkyl-amino-carbonyl,C₁₋₃alkyl-S(O)₀₋₂—C₁₋₂alkyl, carboxyl and hydroxy-substituted-C₁₋₃alkyl;R₄ is selected from the group consisting of hydrogen, amino, C₁₋₃alkyl,cyano, hydroxy-ethyl and halo; or R₃ and R₄ together with the carbonatom to which R₃ and R₄ are attached form a 4 member saturated cyclicring containing an oxygen molecule; R₅ is selected from the groupconsisting of hydrogen, halo, amino, C₁₋₃alkyl-amino-carbonyl, hydroxyand C₁₋₃alkoxy; R₆ is selected from the group consisting of hydrogen,C₁₋₃alkyl, halo, halo-substituted-C₁₋₃alkyl; or R₄ and R₆ together withthe carbon atom to which R₄ and R₆ are attached form 5-6 memberunsaturated ring containing up to 2 heteroatoms selected from O, S andN; wherein said ring is optionally substituted with C₁₋₂alkyl; R₉ isselected from the group consisting of hydrogen and methyl; Y₁ isselected from the group consisting of N and CH; Y₂ is selected from thegroup consisting of N and CH; Y₃ is selected from the group consistingof N and CH; Y₄ is selected from the group consisting of N and CH; Y₅ isselected from the group consisting of N and CH; and Y₆ is selected fromthe group consisting of N and CH; or the pharmaceutically acceptablesalt thereof.
 18. The compound of claim 17 in which: R₁ is selected fromthe group consisting of trifluoromethyl, 2-fluoropropan-2-yl,2-cyanopropan-2-yl and 1,1-difluoroethyl; R₃ is selected from the groupconsisting of hydrogen and methyl, fluoro, methyl-amino-carbonyl,ethyl-amino-carbonyl, methyl-sulfonyl-methyl, carboxyl andhydroxy-ethyl; R₄ is selected from the group consisting of hydrogen,methyl, cyano, amino, hydroxy-ethyl and fluoro; or R₃ and R₄ togetherwith the carbon atom to which R₃ and R₄ are attached form oxetan-3-yl;R₅ is selected from the group consisting of hydrogen, fluoro, amino,methyl-carbonyl-amino, ethyl-carbonyl-amino, hydroxy and methoxy; R₆ isselected from the group consisting of hydrogen, methyl, fluoro andtrifluoromethyl; or R₄ and R₆ together with the carbon atom to which R₄and R₆ are attached form pyrazolyl optionally substituted with methyl;R₉ is selected from the group consisting of hydrogen and methyl; Y₁ isselected from the group consisting of N and CH; Y₂ is CH; Y₃ is CH; Y₄is selected from the group consisting of N and CH; Y₅ is selected fromthe group consisting of N and CH; and Y₆ is selected from the groupconsisting of N and CH; or the pharmaceutically acceptable salt thereof.19. The compound of claim 1, which is a compound of formula (Ic):

in which: R₁ is halo-substituted C₁₋₃alkyl; R₈ is selected from thegroup consisting of hydrogen and C₁₋₃alkyl; R₉ is selected from thegroup consisting of hydrogen and methyl; Y₁ is selected from the groupconsisting of N and CH; Y₂ is selected from the group consisting of Nand CH; Y₃ is selected from the group consisting of N and CH; Y₄ isselected from the group consisting of N and CH; Y₅ is selected from thegroup consisting of N and CH; and Y₆ is selected from the groupconsisting of N and CH; or the pharmaceutically acceptable salt thereof.20. The compound of claim 19 in which: R₁ is selected from the groupconsisting of trifluoromethyl, 2-fluoropropan-2-yl, 2-cyanopropan-2-yland 1,1-difluoroethyl; R₈ is selected from the group consisting ofhydrogen and ethyl; R₉ is selected from the group consisting of hydrogenand methyl; Y₁ is selected from the group consisting of N and CH; Y₂ isCH; Y₃ is CH; Y₄ is selected from the group consisting of N and CH; Y₅is selected from the group consisting of N and CH; and Y₆ is selectedfrom the group consisting of N and CH; or the pharmaceuticallyacceptable salt thereof.
 21. The compound of claim 1, which is acompound of formula (Id):

in which: R₁ is halo-substituted C₁₋₃alkyl; each R₇ is selected from thegroup consisting of hydrogen, C₁₋₂alkoxy-carbonyl and hydroxy-carbonyl;Y₁ is selected from the group consisting of N and CH; Y₂ is CH; Y₃ isCH; and Y₄ is selected from the group consisting of N and CH; or thepharmaceutically acceptable salt thereof.
 22. The compound of claim 21in which: R₁ is selected from the group consisting of trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; each R₇is selected from the group consisting of hydrogen, ethoxy-carbonyl andhydroxy-carbonyl; Y₁ is selected from the group consisting of N and CH;Y₂ is CH; Y₃ is CH; and Y₄ is selected from the group consisting of Nand CH; or the pharmaceutically acceptable salt thereof.
 23. Thecompound of claim 1, which is a compound of formula (Ie):

in which: R₁ is halo-substituted C₁₋₃alkyl; R₃ is selected from thegroup consisting of hydrogen and C₁₋₃alkyl; R₄ is selected from thegroup consisting of hydrogen and C₁₋₃alkyl; Y₁ is selected from thegroup consisting of N and CH; Y₂ is selected from the group consistingof N and CH; Y₃ is selected from the group consisting of N and CH; Y₄ isselected from the group consisting of N and CH; Y₅ is selected from thegroup consisting of N and CH; and Y₆ is selected from the groupconsisting of N and CH; or the pharmaceutically acceptable salt thereof.24. The compound of claim 23 in which: R₁ is selected from the groupconsisting of trifluoromethyl, 2-fluoropropan-2-yl, 2-cyanopropan-2-yland 1,1-difluoroethyl; R₃ is selected from the group consisting ofhydrogen, methyl and ethyl; R₄ is selected from the group consisting ofhydrogen, methyl and ethyl; Y₁ is N; Y₂ is CH; Y₃ is CH; Y₄ is CH; Y₅ isN; and Y₆ is N; or the pharmaceutically acceptable salt thereof.
 25. Thecompound of claim 1, which is a compound of formula (If):

in which: R₁ is selected from the group consisting of trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; R₃ isselected from the group consisting of hydrogen and C₁₋₃alkyl; R₄ isselected from the group consisting of hydrogen and C₁₋₃alkyl; R₅ isselected from the group consisting of hydrogen, halo, amino,C₁₋₃alkyl-amino-carbonyl, hydroxy and C₁₋₃alkoxy; R₆ is selected fromthe group consisting of hydrogen, C₁₋₃alkyl, halo andhalo-substituted-C₁₋₃alkyl; Y₁ is selected from the group consisting ofN and CH; Y₂ is selected from the group consisting of N and CH; Y₃ isselected from the group consisting of N and CH; and Y₄ is selected fromthe group consisting of N and CH; or the pharmaceutically acceptablesalt thereof.
 26. The compound of claim 1, which is a compound offormula (Ig):

in which: R₁ is selected from the group consisting of trifluoromethyl,2-fluoropropan-2-yl, 2-cyanopropan-2-yl and 1,1-difluoroethyl; R₈ isselected from the group consisting of hydrogen and C₁₋₃alkyl; Y₁ isselected from the group consisting of N and CH; Y₂ is selected from thegroup consisting of N and CH; Y₃ is selected from the group consistingof N and CH; Y₄ is selected from the group consisting of N and CH; Y₅ isselected from the group consisting of N and CH; and Y₆ is selected fromthe group consisting of N and CH; or the pharmaceutically acceptablesalt thereof.
 27. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, selected from the compound of any of Examples1-534.
 28. A pharmaceutical composition comprising a compound of claim1, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.
 29. A combination comprising atherapeutically effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof, and one or moretherapeutically active co-agents.
 30. A method of treating a cancer,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the cancer is selected from melanoma,breast cancer, non-small cell lung cancer, lung adenocarcinoma, sarcoma,gastrointestinal stromal tumors, ovarian cancer, colorectal cancer,thyroid cancer and pancreatic cancer.